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Heart failure med undertreatment because of older age common, flouts evidence
, suggests a large cohort study.
About 80% of patients aged 80 years or older were prescribed renin-angiotensin-system inhibitors (RASi) in a multivariate-adjusted analysis of more than 27,000 patients in the Swedish Heart Failure Registry (SwedeHF). In contrast, such drugs – which included angiotensin receptor-neprilysin inhibitors (ARNi), angiotensin receptor blockers, and ACE inhibitors – were prescribed to 95% of patients younger than 70 years.
Similarly, fewer of the oldest patients were offered meds from the two other drug classes core to HF management at the time: Beta blockers and mineralocorticoid receptor antagonists (MRA).
And among those in the 80-and-older age group who were prescribed RASi or beta blockers, their uptitration more often fell short of even half the target dosage, compared with the youngest patients in the analysis.
Physicians may hold back on full guideline-directed medical therapy in their very elderly patients with HFrEF for many reasons, including a perceived likelihood of drug intolerance due to frailty or multiple comorbidities, including renal dysfunction, Davide Stolfo, MD, Karolinska Institutet, Stockholm, and University of Trieste, Italy, told this news organization.
But the current analysis was adjusted for about 80 variables “that in our interpretation may be main reasons for not introducing drugs and using them in the older patients,” he said. They included care setting (that is, inpatient or outpatient), HF severity by several measures, a range of comorbidities, renal dysfunction, and history of serious illness such as cancer.
Even then, age emerged as a significant, independent predictor of medical therapy underuse in the oldest patients. Some physicians apparently see advanced age, by itself, as an “intrinsic reason” not to abide by HFrEF medical therapy recommendations, said Dr. Stolfo, who presented the analysis at HFA 2021, the annual meeting of the Heart Failure Association of the European Society of Cardiology (ESC-HFA), conducted both virtually and live in Florence, Italy.
Most major HF-drug trials have excluded or admitted few patients aged 80 years or older, but “the guidelines recommend treatment regardless of age, and in the trials there has been no influence from age on the effectiveness of drugs,” Dr. Stolfo observed.
Moreover, in a prior SwedeHF analysis with propensity matching, patients with HFrEF aged 80 or older showed steeper reductions in risk for death or HF hospitalization from treatment with RASi than those in younger age groups.
One of the few randomized trials to focus on the very elderly, called SENIORS, enrolled patients aged 70 years and older – the average age was 76 – and saw a significantly reduced risk of death or cardiovascular hospitalization for those assigned to the beta blocker nebivolol. The benefits in the trial, which was conducted 15 years ago, were independent of left ventricular function.
So in the oldest patients, “we could question the need to achieve full dose of an evidence-based drug, but we shouldn’t question the use of these drugs.”
The findings are consistent with a need to individualize medical therapy in senior patients with HFrEF, especially those of more advanced age, some of whom may be robust enough to be managed similarly to younger patients while others who may be less suitable for full guideline-directed medical therapy, Dr. Stolfo said.
Even for those who are more frail or have major comorbidities, drug therapy of HFrEF continues to be important for symptom control even if competing causes of death make it harder to prolong survival, Dr. Stolfo said.
“We should provide to all patients the best strategy they can tolerate,” he said. “If we cannot greatly impact on the long-term survival for these patients, treatment can be aimed to improve the quality of life and keep the patient out of the hospital.”
The analysis was supported by Boehringer Ingelheim. Dr. Stolfo disclosed personal fees from Novartis, Merck, GlaxoSmithKline, and Acceleron.
A version of this article first appeared on Medscape.com.
, suggests a large cohort study.
About 80% of patients aged 80 years or older were prescribed renin-angiotensin-system inhibitors (RASi) in a multivariate-adjusted analysis of more than 27,000 patients in the Swedish Heart Failure Registry (SwedeHF). In contrast, such drugs – which included angiotensin receptor-neprilysin inhibitors (ARNi), angiotensin receptor blockers, and ACE inhibitors – were prescribed to 95% of patients younger than 70 years.
Similarly, fewer of the oldest patients were offered meds from the two other drug classes core to HF management at the time: Beta blockers and mineralocorticoid receptor antagonists (MRA).
And among those in the 80-and-older age group who were prescribed RASi or beta blockers, their uptitration more often fell short of even half the target dosage, compared with the youngest patients in the analysis.
Physicians may hold back on full guideline-directed medical therapy in their very elderly patients with HFrEF for many reasons, including a perceived likelihood of drug intolerance due to frailty or multiple comorbidities, including renal dysfunction, Davide Stolfo, MD, Karolinska Institutet, Stockholm, and University of Trieste, Italy, told this news organization.
But the current analysis was adjusted for about 80 variables “that in our interpretation may be main reasons for not introducing drugs and using them in the older patients,” he said. They included care setting (that is, inpatient or outpatient), HF severity by several measures, a range of comorbidities, renal dysfunction, and history of serious illness such as cancer.
Even then, age emerged as a significant, independent predictor of medical therapy underuse in the oldest patients. Some physicians apparently see advanced age, by itself, as an “intrinsic reason” not to abide by HFrEF medical therapy recommendations, said Dr. Stolfo, who presented the analysis at HFA 2021, the annual meeting of the Heart Failure Association of the European Society of Cardiology (ESC-HFA), conducted both virtually and live in Florence, Italy.
Most major HF-drug trials have excluded or admitted few patients aged 80 years or older, but “the guidelines recommend treatment regardless of age, and in the trials there has been no influence from age on the effectiveness of drugs,” Dr. Stolfo observed.
Moreover, in a prior SwedeHF analysis with propensity matching, patients with HFrEF aged 80 or older showed steeper reductions in risk for death or HF hospitalization from treatment with RASi than those in younger age groups.
One of the few randomized trials to focus on the very elderly, called SENIORS, enrolled patients aged 70 years and older – the average age was 76 – and saw a significantly reduced risk of death or cardiovascular hospitalization for those assigned to the beta blocker nebivolol. The benefits in the trial, which was conducted 15 years ago, were independent of left ventricular function.
So in the oldest patients, “we could question the need to achieve full dose of an evidence-based drug, but we shouldn’t question the use of these drugs.”
The findings are consistent with a need to individualize medical therapy in senior patients with HFrEF, especially those of more advanced age, some of whom may be robust enough to be managed similarly to younger patients while others who may be less suitable for full guideline-directed medical therapy, Dr. Stolfo said.
Even for those who are more frail or have major comorbidities, drug therapy of HFrEF continues to be important for symptom control even if competing causes of death make it harder to prolong survival, Dr. Stolfo said.
“We should provide to all patients the best strategy they can tolerate,” he said. “If we cannot greatly impact on the long-term survival for these patients, treatment can be aimed to improve the quality of life and keep the patient out of the hospital.”
The analysis was supported by Boehringer Ingelheim. Dr. Stolfo disclosed personal fees from Novartis, Merck, GlaxoSmithKline, and Acceleron.
A version of this article first appeared on Medscape.com.
, suggests a large cohort study.
About 80% of patients aged 80 years or older were prescribed renin-angiotensin-system inhibitors (RASi) in a multivariate-adjusted analysis of more than 27,000 patients in the Swedish Heart Failure Registry (SwedeHF). In contrast, such drugs – which included angiotensin receptor-neprilysin inhibitors (ARNi), angiotensin receptor blockers, and ACE inhibitors – were prescribed to 95% of patients younger than 70 years.
Similarly, fewer of the oldest patients were offered meds from the two other drug classes core to HF management at the time: Beta blockers and mineralocorticoid receptor antagonists (MRA).
And among those in the 80-and-older age group who were prescribed RASi or beta blockers, their uptitration more often fell short of even half the target dosage, compared with the youngest patients in the analysis.
Physicians may hold back on full guideline-directed medical therapy in their very elderly patients with HFrEF for many reasons, including a perceived likelihood of drug intolerance due to frailty or multiple comorbidities, including renal dysfunction, Davide Stolfo, MD, Karolinska Institutet, Stockholm, and University of Trieste, Italy, told this news organization.
But the current analysis was adjusted for about 80 variables “that in our interpretation may be main reasons for not introducing drugs and using them in the older patients,” he said. They included care setting (that is, inpatient or outpatient), HF severity by several measures, a range of comorbidities, renal dysfunction, and history of serious illness such as cancer.
Even then, age emerged as a significant, independent predictor of medical therapy underuse in the oldest patients. Some physicians apparently see advanced age, by itself, as an “intrinsic reason” not to abide by HFrEF medical therapy recommendations, said Dr. Stolfo, who presented the analysis at HFA 2021, the annual meeting of the Heart Failure Association of the European Society of Cardiology (ESC-HFA), conducted both virtually and live in Florence, Italy.
Most major HF-drug trials have excluded or admitted few patients aged 80 years or older, but “the guidelines recommend treatment regardless of age, and in the trials there has been no influence from age on the effectiveness of drugs,” Dr. Stolfo observed.
Moreover, in a prior SwedeHF analysis with propensity matching, patients with HFrEF aged 80 or older showed steeper reductions in risk for death or HF hospitalization from treatment with RASi than those in younger age groups.
One of the few randomized trials to focus on the very elderly, called SENIORS, enrolled patients aged 70 years and older – the average age was 76 – and saw a significantly reduced risk of death or cardiovascular hospitalization for those assigned to the beta blocker nebivolol. The benefits in the trial, which was conducted 15 years ago, were independent of left ventricular function.
So in the oldest patients, “we could question the need to achieve full dose of an evidence-based drug, but we shouldn’t question the use of these drugs.”
The findings are consistent with a need to individualize medical therapy in senior patients with HFrEF, especially those of more advanced age, some of whom may be robust enough to be managed similarly to younger patients while others who may be less suitable for full guideline-directed medical therapy, Dr. Stolfo said.
Even for those who are more frail or have major comorbidities, drug therapy of HFrEF continues to be important for symptom control even if competing causes of death make it harder to prolong survival, Dr. Stolfo said.
“We should provide to all patients the best strategy they can tolerate,” he said. “If we cannot greatly impact on the long-term survival for these patients, treatment can be aimed to improve the quality of life and keep the patient out of the hospital.”
The analysis was supported by Boehringer Ingelheim. Dr. Stolfo disclosed personal fees from Novartis, Merck, GlaxoSmithKline, and Acceleron.
A version of this article first appeared on Medscape.com.
Chronic stress and genetics can raise the risk of Alzheimer’s disease
The researchers also proposed a mechanism to account for how genetic factors may affect HPA axis reactivity and lead to inflammation, which is a core component of neurodegeneration.
“Chronic stress can impact the way immune cells in the brain function and increase inflammation. Genetic variants within that stress response can further affect the function of immune cells,” lead author Ayeisha Milligan Armstrong, a PhD candidate at Curtin Health Innovation Research Institute in Perth, Australia, said in an interview.
The findings were published online June 22 in Biological Reviews).
Research has found that long-term stress during early and mid-life is increasingly associated with cognitive decline and neurodegeneration. There is already evidence to suggest that chronic stress is a risk factor for the “sporadic” or late-onset subtype of Alzheimer’s disease.
A cascade of events
Stress activates the HPA, which in turn regulates bodily levels of cortisol, a glucocorticoid stress hormone. Increased levels of cortisol are frequently observed in patients with Alzheimer’s disease and “make a major contribution to the disease process,” the authors wrote. For example, the hippocampus – a part of the brain involved in processing and forming memories – has numerous glucocorticoid receptors and is “therefore particularly sensitive to the effects of glucocorticoids.” However, the molecular mechanisms involved remain poorly understood.
“There is an intimate interplay between exposure to chronic stress and pathways influencing the body’s reaction to such stress,” senior author David Groth, PhD, said in a statement. Dr. Groth is an associate professor at Curtin University in Perth, Australia.
There is variation between individuals with regard to how sensitive they are to stress and glucocorticoid responses. Environmental factors such as stress are thought to be at least partly responsible, as are genetic factors such as genetic polymorphisms and epigenetics. “Genetic variations within these pathways can influence the way the brain’s immune system behaves, leading to a dysfunctional response. In the brain, this leads to a chronic disruption of normal brain processes, increasing the risk of subsequent neurodegeneration and ultimately dementia,” Dr. Groth said.
The researchers suggested that these variations may prime the immune cells of the brain, the microglia, to cause inflammation in the brain. Normally, microglia are involved in monitoring the brain tissue for and responding to damage and infections to keep the brain healthy. However, in an inflammatory state, the microglia instead contribute to a “more neurotoxic environment through the production of proinflammatory cytokines, altered synaptic pruning, and the reduced production of protective neurotrophic factors,” the authors wrote. Microglia may also promote the accumulation of amyloid beta and tau protein, which damage the brain tissue and can cause neurodegeneration. There are different groups of microglia in the brain, each of which may respond differently to genetic and environmental stressors.
“Genome-wide association studies have found that of the genes identified as being associated with Alzheimer’s disease, 60.5% are expressed in microglia,” the authors noted.
To connect the roles of chronic stress and brain inflammation in Alzheimer’s disease, the researchers proposed a “two-hit” hypothesis: Early or mid-life exposure to stress primes the microglia to enter an inflammatory state in response to a secondary stimulus later in life.
Pay attention to stress
For clinicians, this paper highlights the importance of managing stress in patients and their families.
“Clinicians need to be attuned to the effects of stress on patients and their caregivers, and how that [stress] can affect their morbidity and mortality,” Cynthia Munro, PhD, associate professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, said in an interview. She added that attention must be paid to modifiable risk factors such as poor sleep and diet.
Although managing stress is important, that doesn’t mean that everyone who’s experienced chronic stress will develop Alzheimer’s disease. “Chronic stress can alter the HPA axis but it doesn’t necessarily do so in everyone. A cascade of events needs to occur,” said Dr. Munro. “People should always try to reduce the effects of stress to the extent that they can. Stress can lead to a whole host of negative health outcomes, not just Alzheimer’s disease.”
Next steps
Moving forward, the researchers plan to further investigate the molecular mechanisms responsible for the role of stress in Alzheimer’s disease and how genetic variants affect neurodegeneration, Ms. Armstrong said. Ultimately, understanding how stress and genetics contribute to Alzheimer’s disease may lead to the identification of possible therapeutic targets.
Ms. Armstrong and Dr. Munro declared no relevant financial relationships. The study was independently funded.
The researchers also proposed a mechanism to account for how genetic factors may affect HPA axis reactivity and lead to inflammation, which is a core component of neurodegeneration.
“Chronic stress can impact the way immune cells in the brain function and increase inflammation. Genetic variants within that stress response can further affect the function of immune cells,” lead author Ayeisha Milligan Armstrong, a PhD candidate at Curtin Health Innovation Research Institute in Perth, Australia, said in an interview.
The findings were published online June 22 in Biological Reviews).
Research has found that long-term stress during early and mid-life is increasingly associated with cognitive decline and neurodegeneration. There is already evidence to suggest that chronic stress is a risk factor for the “sporadic” or late-onset subtype of Alzheimer’s disease.
A cascade of events
Stress activates the HPA, which in turn regulates bodily levels of cortisol, a glucocorticoid stress hormone. Increased levels of cortisol are frequently observed in patients with Alzheimer’s disease and “make a major contribution to the disease process,” the authors wrote. For example, the hippocampus – a part of the brain involved in processing and forming memories – has numerous glucocorticoid receptors and is “therefore particularly sensitive to the effects of glucocorticoids.” However, the molecular mechanisms involved remain poorly understood.
“There is an intimate interplay between exposure to chronic stress and pathways influencing the body’s reaction to such stress,” senior author David Groth, PhD, said in a statement. Dr. Groth is an associate professor at Curtin University in Perth, Australia.
There is variation between individuals with regard to how sensitive they are to stress and glucocorticoid responses. Environmental factors such as stress are thought to be at least partly responsible, as are genetic factors such as genetic polymorphisms and epigenetics. “Genetic variations within these pathways can influence the way the brain’s immune system behaves, leading to a dysfunctional response. In the brain, this leads to a chronic disruption of normal brain processes, increasing the risk of subsequent neurodegeneration and ultimately dementia,” Dr. Groth said.
The researchers suggested that these variations may prime the immune cells of the brain, the microglia, to cause inflammation in the brain. Normally, microglia are involved in monitoring the brain tissue for and responding to damage and infections to keep the brain healthy. However, in an inflammatory state, the microglia instead contribute to a “more neurotoxic environment through the production of proinflammatory cytokines, altered synaptic pruning, and the reduced production of protective neurotrophic factors,” the authors wrote. Microglia may also promote the accumulation of amyloid beta and tau protein, which damage the brain tissue and can cause neurodegeneration. There are different groups of microglia in the brain, each of which may respond differently to genetic and environmental stressors.
“Genome-wide association studies have found that of the genes identified as being associated with Alzheimer’s disease, 60.5% are expressed in microglia,” the authors noted.
To connect the roles of chronic stress and brain inflammation in Alzheimer’s disease, the researchers proposed a “two-hit” hypothesis: Early or mid-life exposure to stress primes the microglia to enter an inflammatory state in response to a secondary stimulus later in life.
Pay attention to stress
For clinicians, this paper highlights the importance of managing stress in patients and their families.
“Clinicians need to be attuned to the effects of stress on patients and their caregivers, and how that [stress] can affect their morbidity and mortality,” Cynthia Munro, PhD, associate professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, said in an interview. She added that attention must be paid to modifiable risk factors such as poor sleep and diet.
Although managing stress is important, that doesn’t mean that everyone who’s experienced chronic stress will develop Alzheimer’s disease. “Chronic stress can alter the HPA axis but it doesn’t necessarily do so in everyone. A cascade of events needs to occur,” said Dr. Munro. “People should always try to reduce the effects of stress to the extent that they can. Stress can lead to a whole host of negative health outcomes, not just Alzheimer’s disease.”
Next steps
Moving forward, the researchers plan to further investigate the molecular mechanisms responsible for the role of stress in Alzheimer’s disease and how genetic variants affect neurodegeneration, Ms. Armstrong said. Ultimately, understanding how stress and genetics contribute to Alzheimer’s disease may lead to the identification of possible therapeutic targets.
Ms. Armstrong and Dr. Munro declared no relevant financial relationships. The study was independently funded.
The researchers also proposed a mechanism to account for how genetic factors may affect HPA axis reactivity and lead to inflammation, which is a core component of neurodegeneration.
“Chronic stress can impact the way immune cells in the brain function and increase inflammation. Genetic variants within that stress response can further affect the function of immune cells,” lead author Ayeisha Milligan Armstrong, a PhD candidate at Curtin Health Innovation Research Institute in Perth, Australia, said in an interview.
The findings were published online June 22 in Biological Reviews).
Research has found that long-term stress during early and mid-life is increasingly associated with cognitive decline and neurodegeneration. There is already evidence to suggest that chronic stress is a risk factor for the “sporadic” or late-onset subtype of Alzheimer’s disease.
A cascade of events
Stress activates the HPA, which in turn regulates bodily levels of cortisol, a glucocorticoid stress hormone. Increased levels of cortisol are frequently observed in patients with Alzheimer’s disease and “make a major contribution to the disease process,” the authors wrote. For example, the hippocampus – a part of the brain involved in processing and forming memories – has numerous glucocorticoid receptors and is “therefore particularly sensitive to the effects of glucocorticoids.” However, the molecular mechanisms involved remain poorly understood.
“There is an intimate interplay between exposure to chronic stress and pathways influencing the body’s reaction to such stress,” senior author David Groth, PhD, said in a statement. Dr. Groth is an associate professor at Curtin University in Perth, Australia.
There is variation between individuals with regard to how sensitive they are to stress and glucocorticoid responses. Environmental factors such as stress are thought to be at least partly responsible, as are genetic factors such as genetic polymorphisms and epigenetics. “Genetic variations within these pathways can influence the way the brain’s immune system behaves, leading to a dysfunctional response. In the brain, this leads to a chronic disruption of normal brain processes, increasing the risk of subsequent neurodegeneration and ultimately dementia,” Dr. Groth said.
The researchers suggested that these variations may prime the immune cells of the brain, the microglia, to cause inflammation in the brain. Normally, microglia are involved in monitoring the brain tissue for and responding to damage and infections to keep the brain healthy. However, in an inflammatory state, the microglia instead contribute to a “more neurotoxic environment through the production of proinflammatory cytokines, altered synaptic pruning, and the reduced production of protective neurotrophic factors,” the authors wrote. Microglia may also promote the accumulation of amyloid beta and tau protein, which damage the brain tissue and can cause neurodegeneration. There are different groups of microglia in the brain, each of which may respond differently to genetic and environmental stressors.
“Genome-wide association studies have found that of the genes identified as being associated with Alzheimer’s disease, 60.5% are expressed in microglia,” the authors noted.
To connect the roles of chronic stress and brain inflammation in Alzheimer’s disease, the researchers proposed a “two-hit” hypothesis: Early or mid-life exposure to stress primes the microglia to enter an inflammatory state in response to a secondary stimulus later in life.
Pay attention to stress
For clinicians, this paper highlights the importance of managing stress in patients and their families.
“Clinicians need to be attuned to the effects of stress on patients and their caregivers, and how that [stress] can affect their morbidity and mortality,” Cynthia Munro, PhD, associate professor of psychiatry and behavioral sciences at Johns Hopkins University, Baltimore, said in an interview. She added that attention must be paid to modifiable risk factors such as poor sleep and diet.
Although managing stress is important, that doesn’t mean that everyone who’s experienced chronic stress will develop Alzheimer’s disease. “Chronic stress can alter the HPA axis but it doesn’t necessarily do so in everyone. A cascade of events needs to occur,” said Dr. Munro. “People should always try to reduce the effects of stress to the extent that they can. Stress can lead to a whole host of negative health outcomes, not just Alzheimer’s disease.”
Next steps
Moving forward, the researchers plan to further investigate the molecular mechanisms responsible for the role of stress in Alzheimer’s disease and how genetic variants affect neurodegeneration, Ms. Armstrong said. Ultimately, understanding how stress and genetics contribute to Alzheimer’s disease may lead to the identification of possible therapeutic targets.
Ms. Armstrong and Dr. Munro declared no relevant financial relationships. The study was independently funded.
FROM BIOLOGICAL REVIEWS
Hearing loss tied to decline in physical functioning
published online in JAMA Network Open.
Hearing loss is associated with slower gait and, in particular, worse balance, the data suggest.
“Because hearing impairment is amenable to prevention and management, it potentially serves as a target for interventions to slow physical decline with aging,” the researchers said.
To examine how hearing impairment relates to physical function in older adults, Pablo Martinez-Amezcua, MD, PhD, MHS, a researcher in the department of epidemiology at Johns Hopkins University, Baltimore, and colleagues analyzed data from the ongoing Atherosclerosis Risk in Communities (ARIC) study.
ARIC initially enrolled more than 15,000 adults in Maryland, Minnesota, Mississippi, and North Carolina between 1987 and 1989. In the present study, the researchers focused on data from 2,956 participants who attended a study visit between 2016 and 2017, during which researchers assessed their hearing using pure tone audiometry.
Hearing-study participants had an average age of 79 years, about 58% were women, and 80% were White. Approximately 33% of the participants had normal hearing, 40% had mild hearing impairment, 23% had moderate hearing impairment, and 4% had severe hearing impairment.
Participants had also undergone assessment of physical functioning at study visits between 2011 and 2019, including a fast-paced 2-minute walk test to measure their walking endurance. Another assessment, the Short Physical Performance Battery (SPPB), tests balance, gait speed, and chair stands (seated participants stand up and sit back down five times as quickly as possible while their arms are crossed).
Dr. Martinez-Amezcua and colleagues found that severe hearing impairment was associated with a lower average SPPB score compared with normal hearing in a regression analysis. Specifically, compared with those with normal hearing, participants with severe hearing impairment were more likely to have low scores on the SPPB (odds ratio, 2.72), balance (OR, 2.72), and gait speed (OR, 2.16).
However, hearing impairment was not significantly associated with the chair stand test results. The researchers note that chair stands may rely more on strength, whereas balance and gait speed may rely more on coordination and movement.
The team also found that people with worse hearing tended to walk a shorter distance during the 2-minute walk test. Compared with participants with normal hearing, participants with moderate hearing impairment walked 2.81 meters less and those with severe hearing impairment walked 5.31 meters less on average, after adjustment for variables including age, sex, and health conditions.
Participants with hearing impairment also tended to have faster declines in physical function over time.
Various mechanisms could explain associations between hearing and physical function, the authors said. For example, an underlying condition such as cardiovascular disease might affect both hearing and physical function. Damage to the inner ear could affect vestibular and auditory systems at the same time. In addition, hearing impairment may relate to cognition, depression, or social isolation, which could influence physical activity.
“Age-related hearing loss is traditionally seen as a barrier for communication,” Dr. Martinez-Amezcua told this news organization. “In the past decade, research on the consequences of hearing loss has identified it as a risk factor for cognitive decline and dementia. Our findings contribute to our understanding of other negative outcomes associated with hearing loss.”
Randomized clinical trials are the best way to assess whether addressing hearing loss might improve physical function, Dr. Martinez-Amezcua said. “Currently there is one clinical trial (ACHIEVE) that will, among other outcomes, study the impact of hearing aids on cognitive and physical function,” he said.
Although interventions may not reverse hearing loss, hearing rehabilitation strategies, including hearing aids and cochlear implants, may help, he added. Educating caregivers and changing a person’s environment can also reduce the effects hearing loss has on daily life, Dr. Martinez-Amezcua said.
“We rely so much in our sense of vision for activities of daily living that we tend to underestimate how important hearing is, and the consequences of hearing loss go beyond having trouble communicating with someone,” he said.
This study and prior research “raise the intriguing idea that hearing may provide essential information to the neural circuits underpinning movement in our environment and that correction for hearing loss may help promote physical well-being,” Willa D. Brenowitz, PhD, MPH, and Margaret I. Wallhagen, PhD, GNP-BC, both at the University of California, San Francisco, wrote in an accompanying commentary. “While this hypothesis is appealing and warrants further investigation, there are multiple other potential explanations of such an association, including potential sources of bias that may affect observational studies such as this one.”
Beyond treating hearing loss, interventions such as physical therapy or tai chi may benefit patients, they suggested.
Because many changes occur during older age, it can be difficult to understand which factor is influencing another, Dr. Brenowitz said in an interview. There are potentially relevant mechanisms through which hearing could affect cognition and physical functioning. Still another explanation could be that some people are “aging in a faster way” than others, Dr. Brenowitz said.
Dr. Martinez-Amezcua and a coauthor disclosed receiving sponsorship from the Cochlear Center for Hearing and Public Health. Another author, Frank R. Lin, MD, PhD, directs the research center, which is partly funded by a philanthropic gift from Cochlear to the Johns Hopkins Bloomberg School of Public Health. Dr. Lin also disclosed personal fees from Frequency Therapeutics and Caption Call. One author serves on a scientific advisory board for Shoebox and Good Machine Studio.
Dr. Wallhagen has served on the board of trustees of the Hearing Loss Association of America and is a member of the board of the Hearing Loss Association of America–California. Dr. Wallhagen also received funding for a pilot project on the impact of hearing loss on communication in the context of chronic serious illness from the National Palliative Care Research Center outside the submitted work.
A version of this article first appeared on Medscape.com.
published online in JAMA Network Open.
Hearing loss is associated with slower gait and, in particular, worse balance, the data suggest.
“Because hearing impairment is amenable to prevention and management, it potentially serves as a target for interventions to slow physical decline with aging,” the researchers said.
To examine how hearing impairment relates to physical function in older adults, Pablo Martinez-Amezcua, MD, PhD, MHS, a researcher in the department of epidemiology at Johns Hopkins University, Baltimore, and colleagues analyzed data from the ongoing Atherosclerosis Risk in Communities (ARIC) study.
ARIC initially enrolled more than 15,000 adults in Maryland, Minnesota, Mississippi, and North Carolina between 1987 and 1989. In the present study, the researchers focused on data from 2,956 participants who attended a study visit between 2016 and 2017, during which researchers assessed their hearing using pure tone audiometry.
Hearing-study participants had an average age of 79 years, about 58% were women, and 80% were White. Approximately 33% of the participants had normal hearing, 40% had mild hearing impairment, 23% had moderate hearing impairment, and 4% had severe hearing impairment.
Participants had also undergone assessment of physical functioning at study visits between 2011 and 2019, including a fast-paced 2-minute walk test to measure their walking endurance. Another assessment, the Short Physical Performance Battery (SPPB), tests balance, gait speed, and chair stands (seated participants stand up and sit back down five times as quickly as possible while their arms are crossed).
Dr. Martinez-Amezcua and colleagues found that severe hearing impairment was associated with a lower average SPPB score compared with normal hearing in a regression analysis. Specifically, compared with those with normal hearing, participants with severe hearing impairment were more likely to have low scores on the SPPB (odds ratio, 2.72), balance (OR, 2.72), and gait speed (OR, 2.16).
However, hearing impairment was not significantly associated with the chair stand test results. The researchers note that chair stands may rely more on strength, whereas balance and gait speed may rely more on coordination and movement.
The team also found that people with worse hearing tended to walk a shorter distance during the 2-minute walk test. Compared with participants with normal hearing, participants with moderate hearing impairment walked 2.81 meters less and those with severe hearing impairment walked 5.31 meters less on average, after adjustment for variables including age, sex, and health conditions.
Participants with hearing impairment also tended to have faster declines in physical function over time.
Various mechanisms could explain associations between hearing and physical function, the authors said. For example, an underlying condition such as cardiovascular disease might affect both hearing and physical function. Damage to the inner ear could affect vestibular and auditory systems at the same time. In addition, hearing impairment may relate to cognition, depression, or social isolation, which could influence physical activity.
“Age-related hearing loss is traditionally seen as a barrier for communication,” Dr. Martinez-Amezcua told this news organization. “In the past decade, research on the consequences of hearing loss has identified it as a risk factor for cognitive decline and dementia. Our findings contribute to our understanding of other negative outcomes associated with hearing loss.”
Randomized clinical trials are the best way to assess whether addressing hearing loss might improve physical function, Dr. Martinez-Amezcua said. “Currently there is one clinical trial (ACHIEVE) that will, among other outcomes, study the impact of hearing aids on cognitive and physical function,” he said.
Although interventions may not reverse hearing loss, hearing rehabilitation strategies, including hearing aids and cochlear implants, may help, he added. Educating caregivers and changing a person’s environment can also reduce the effects hearing loss has on daily life, Dr. Martinez-Amezcua said.
“We rely so much in our sense of vision for activities of daily living that we tend to underestimate how important hearing is, and the consequences of hearing loss go beyond having trouble communicating with someone,” he said.
This study and prior research “raise the intriguing idea that hearing may provide essential information to the neural circuits underpinning movement in our environment and that correction for hearing loss may help promote physical well-being,” Willa D. Brenowitz, PhD, MPH, and Margaret I. Wallhagen, PhD, GNP-BC, both at the University of California, San Francisco, wrote in an accompanying commentary. “While this hypothesis is appealing and warrants further investigation, there are multiple other potential explanations of such an association, including potential sources of bias that may affect observational studies such as this one.”
Beyond treating hearing loss, interventions such as physical therapy or tai chi may benefit patients, they suggested.
Because many changes occur during older age, it can be difficult to understand which factor is influencing another, Dr. Brenowitz said in an interview. There are potentially relevant mechanisms through which hearing could affect cognition and physical functioning. Still another explanation could be that some people are “aging in a faster way” than others, Dr. Brenowitz said.
Dr. Martinez-Amezcua and a coauthor disclosed receiving sponsorship from the Cochlear Center for Hearing and Public Health. Another author, Frank R. Lin, MD, PhD, directs the research center, which is partly funded by a philanthropic gift from Cochlear to the Johns Hopkins Bloomberg School of Public Health. Dr. Lin also disclosed personal fees from Frequency Therapeutics and Caption Call. One author serves on a scientific advisory board for Shoebox and Good Machine Studio.
Dr. Wallhagen has served on the board of trustees of the Hearing Loss Association of America and is a member of the board of the Hearing Loss Association of America–California. Dr. Wallhagen also received funding for a pilot project on the impact of hearing loss on communication in the context of chronic serious illness from the National Palliative Care Research Center outside the submitted work.
A version of this article first appeared on Medscape.com.
published online in JAMA Network Open.
Hearing loss is associated with slower gait and, in particular, worse balance, the data suggest.
“Because hearing impairment is amenable to prevention and management, it potentially serves as a target for interventions to slow physical decline with aging,” the researchers said.
To examine how hearing impairment relates to physical function in older adults, Pablo Martinez-Amezcua, MD, PhD, MHS, a researcher in the department of epidemiology at Johns Hopkins University, Baltimore, and colleagues analyzed data from the ongoing Atherosclerosis Risk in Communities (ARIC) study.
ARIC initially enrolled more than 15,000 adults in Maryland, Minnesota, Mississippi, and North Carolina between 1987 and 1989. In the present study, the researchers focused on data from 2,956 participants who attended a study visit between 2016 and 2017, during which researchers assessed their hearing using pure tone audiometry.
Hearing-study participants had an average age of 79 years, about 58% were women, and 80% were White. Approximately 33% of the participants had normal hearing, 40% had mild hearing impairment, 23% had moderate hearing impairment, and 4% had severe hearing impairment.
Participants had also undergone assessment of physical functioning at study visits between 2011 and 2019, including a fast-paced 2-minute walk test to measure their walking endurance. Another assessment, the Short Physical Performance Battery (SPPB), tests balance, gait speed, and chair stands (seated participants stand up and sit back down five times as quickly as possible while their arms are crossed).
Dr. Martinez-Amezcua and colleagues found that severe hearing impairment was associated with a lower average SPPB score compared with normal hearing in a regression analysis. Specifically, compared with those with normal hearing, participants with severe hearing impairment were more likely to have low scores on the SPPB (odds ratio, 2.72), balance (OR, 2.72), and gait speed (OR, 2.16).
However, hearing impairment was not significantly associated with the chair stand test results. The researchers note that chair stands may rely more on strength, whereas balance and gait speed may rely more on coordination and movement.
The team also found that people with worse hearing tended to walk a shorter distance during the 2-minute walk test. Compared with participants with normal hearing, participants with moderate hearing impairment walked 2.81 meters less and those with severe hearing impairment walked 5.31 meters less on average, after adjustment for variables including age, sex, and health conditions.
Participants with hearing impairment also tended to have faster declines in physical function over time.
Various mechanisms could explain associations between hearing and physical function, the authors said. For example, an underlying condition such as cardiovascular disease might affect both hearing and physical function. Damage to the inner ear could affect vestibular and auditory systems at the same time. In addition, hearing impairment may relate to cognition, depression, or social isolation, which could influence physical activity.
“Age-related hearing loss is traditionally seen as a barrier for communication,” Dr. Martinez-Amezcua told this news organization. “In the past decade, research on the consequences of hearing loss has identified it as a risk factor for cognitive decline and dementia. Our findings contribute to our understanding of other negative outcomes associated with hearing loss.”
Randomized clinical trials are the best way to assess whether addressing hearing loss might improve physical function, Dr. Martinez-Amezcua said. “Currently there is one clinical trial (ACHIEVE) that will, among other outcomes, study the impact of hearing aids on cognitive and physical function,” he said.
Although interventions may not reverse hearing loss, hearing rehabilitation strategies, including hearing aids and cochlear implants, may help, he added. Educating caregivers and changing a person’s environment can also reduce the effects hearing loss has on daily life, Dr. Martinez-Amezcua said.
“We rely so much in our sense of vision for activities of daily living that we tend to underestimate how important hearing is, and the consequences of hearing loss go beyond having trouble communicating with someone,” he said.
This study and prior research “raise the intriguing idea that hearing may provide essential information to the neural circuits underpinning movement in our environment and that correction for hearing loss may help promote physical well-being,” Willa D. Brenowitz, PhD, MPH, and Margaret I. Wallhagen, PhD, GNP-BC, both at the University of California, San Francisco, wrote in an accompanying commentary. “While this hypothesis is appealing and warrants further investigation, there are multiple other potential explanations of such an association, including potential sources of bias that may affect observational studies such as this one.”
Beyond treating hearing loss, interventions such as physical therapy or tai chi may benefit patients, they suggested.
Because many changes occur during older age, it can be difficult to understand which factor is influencing another, Dr. Brenowitz said in an interview. There are potentially relevant mechanisms through which hearing could affect cognition and physical functioning. Still another explanation could be that some people are “aging in a faster way” than others, Dr. Brenowitz said.
Dr. Martinez-Amezcua and a coauthor disclosed receiving sponsorship from the Cochlear Center for Hearing and Public Health. Another author, Frank R. Lin, MD, PhD, directs the research center, which is partly funded by a philanthropic gift from Cochlear to the Johns Hopkins Bloomberg School of Public Health. Dr. Lin also disclosed personal fees from Frequency Therapeutics and Caption Call. One author serves on a scientific advisory board for Shoebox and Good Machine Studio.
Dr. Wallhagen has served on the board of trustees of the Hearing Loss Association of America and is a member of the board of the Hearing Loss Association of America–California. Dr. Wallhagen also received funding for a pilot project on the impact of hearing loss on communication in the context of chronic serious illness from the National Palliative Care Research Center outside the submitted work.
A version of this article first appeared on Medscape.com.
FDA fast-tracks lecanemab for Alzheimer’s disease
Lecanemab (formerly BAN2401) is a humanized monoclonal antibody that selectively binds to large, soluble aggregated Abeta protofibrils. The antibody was developed following the discovery of a mutation in amyloid precursor protein that leads to a form of Alzheimer’s disease that is marked by particularly high levels of Abeta protofibrils.
“As such, lecanemab may have the potential to have an effect on disease pathology and to slow down the progression of the disease,” Eisai and Biogen said in a joint news release.
The breakthrough therapy designation for lecanemab is based on results of a randomized, double-blind, phase 2b proof-of-concept study published April 17 in Alzheimer’s Research & Therapy.
The study enrolled 856 patients with mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease with confirmed presence of amyloid pathology.
At the highest doses, treatment with lecanemab led to a reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints.
Phase 3 testing underway
In March, Eisai and Biogen completed enrollment in a phase 3 study designed to confirm the safety and efficacy of lecanemab in patients with symptomatic early Alzheimer’s disease.
The CLARITY AD study includes 1,795 patients with early Alzheimer’s disease, and initial results are expected by the end of September 2022. The core study will compare lecanemab against placebo on the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 18 months. The study will also evaluate the long-term safety and tolerability of lecanemab in the extension phase and whether the long-term effects of lecanemab, as measured by the CDR-SB at the end of the core study, are maintained over time.
Additionally, the phase 3 AHEAD 3-45 clinical study is currently exploring lecanemab in adults with preclinical Alzheimer’s disease (clinically normal but with intermediate or elevated brain amyloid).
On June 7, the FDA – amid significant controversy – approved aducanumab (Aduhelm), the first anti-amyloid agent for the treatment Alzheimer’s disease, disregarding the recommendation by its own advisory panel not to approve the drug. Three members of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee subsequently resigned in protest following the agency’s approval of aducanumab.
In addition, the high-profile consumer advocacy group Public Citizen sent a letter to the secretary of the U.S. Department of Health & Human Services demanding the removal of three FDA officials, including acting FDA Commissioner Janet Woodcock, MD.
A version of this article first appeared on Medscape.com.
Lecanemab (formerly BAN2401) is a humanized monoclonal antibody that selectively binds to large, soluble aggregated Abeta protofibrils. The antibody was developed following the discovery of a mutation in amyloid precursor protein that leads to a form of Alzheimer’s disease that is marked by particularly high levels of Abeta protofibrils.
“As such, lecanemab may have the potential to have an effect on disease pathology and to slow down the progression of the disease,” Eisai and Biogen said in a joint news release.
The breakthrough therapy designation for lecanemab is based on results of a randomized, double-blind, phase 2b proof-of-concept study published April 17 in Alzheimer’s Research & Therapy.
The study enrolled 856 patients with mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease with confirmed presence of amyloid pathology.
At the highest doses, treatment with lecanemab led to a reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints.
Phase 3 testing underway
In March, Eisai and Biogen completed enrollment in a phase 3 study designed to confirm the safety and efficacy of lecanemab in patients with symptomatic early Alzheimer’s disease.
The CLARITY AD study includes 1,795 patients with early Alzheimer’s disease, and initial results are expected by the end of September 2022. The core study will compare lecanemab against placebo on the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 18 months. The study will also evaluate the long-term safety and tolerability of lecanemab in the extension phase and whether the long-term effects of lecanemab, as measured by the CDR-SB at the end of the core study, are maintained over time.
Additionally, the phase 3 AHEAD 3-45 clinical study is currently exploring lecanemab in adults with preclinical Alzheimer’s disease (clinically normal but with intermediate or elevated brain amyloid).
On June 7, the FDA – amid significant controversy – approved aducanumab (Aduhelm), the first anti-amyloid agent for the treatment Alzheimer’s disease, disregarding the recommendation by its own advisory panel not to approve the drug. Three members of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee subsequently resigned in protest following the agency’s approval of aducanumab.
In addition, the high-profile consumer advocacy group Public Citizen sent a letter to the secretary of the U.S. Department of Health & Human Services demanding the removal of three FDA officials, including acting FDA Commissioner Janet Woodcock, MD.
A version of this article first appeared on Medscape.com.
Lecanemab (formerly BAN2401) is a humanized monoclonal antibody that selectively binds to large, soluble aggregated Abeta protofibrils. The antibody was developed following the discovery of a mutation in amyloid precursor protein that leads to a form of Alzheimer’s disease that is marked by particularly high levels of Abeta protofibrils.
“As such, lecanemab may have the potential to have an effect on disease pathology and to slow down the progression of the disease,” Eisai and Biogen said in a joint news release.
The breakthrough therapy designation for lecanemab is based on results of a randomized, double-blind, phase 2b proof-of-concept study published April 17 in Alzheimer’s Research & Therapy.
The study enrolled 856 patients with mild cognitive impairment (MCI) due to Alzheimer’s disease and mild Alzheimer’s disease with confirmed presence of amyloid pathology.
At the highest doses, treatment with lecanemab led to a reduction in brain amyloid accompanied by a consistent reduction of clinical decline across several clinical and biomarker endpoints.
Phase 3 testing underway
In March, Eisai and Biogen completed enrollment in a phase 3 study designed to confirm the safety and efficacy of lecanemab in patients with symptomatic early Alzheimer’s disease.
The CLARITY AD study includes 1,795 patients with early Alzheimer’s disease, and initial results are expected by the end of September 2022. The core study will compare lecanemab against placebo on the change from baseline in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) at 18 months. The study will also evaluate the long-term safety and tolerability of lecanemab in the extension phase and whether the long-term effects of lecanemab, as measured by the CDR-SB at the end of the core study, are maintained over time.
Additionally, the phase 3 AHEAD 3-45 clinical study is currently exploring lecanemab in adults with preclinical Alzheimer’s disease (clinically normal but with intermediate or elevated brain amyloid).
On June 7, the FDA – amid significant controversy – approved aducanumab (Aduhelm), the first anti-amyloid agent for the treatment Alzheimer’s disease, disregarding the recommendation by its own advisory panel not to approve the drug. Three members of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee subsequently resigned in protest following the agency’s approval of aducanumab.
In addition, the high-profile consumer advocacy group Public Citizen sent a letter to the secretary of the U.S. Department of Health & Human Services demanding the removal of three FDA officials, including acting FDA Commissioner Janet Woodcock, MD.
A version of this article first appeared on Medscape.com.
Stopping statins linked to death, CV events in elderly
Deprescribing may help in reducing inappropriate medication use and adverse events, but for cardiovascular care in the elderly, eliminating statins among patients taking other medications may have negative effects that far outweigh the benefits, a new study suggests.
In a large cohort study, researchers found that the withdrawal of statins from an elderly population receiving polypharmacy was associated with an increase in the risk for hospital admission for heart failure and any cardiovascular outcome, as well as death from any cause.
Statins are “lifesaving” drugs, and “according to the findings of our study, the discontinuation of this therapy has significant effects,” lead study author Federico Rea, PhD, research fellow, Laboratory of Healthcare Research and Pharmacoepidemiology, the department of statistics and quantitative methods, the University of Milano-Bicocca, said in an interview.
The article was published online June 14, 2021, in JAMA Network Open.
Negative clinical consequences, including adverse drug reactions leading to hospitalizations, are causing more physicians to consider deprescribing as a way to reduce problems associated with polypharmacy, the researchers noted.
Statins are “the most widely prescribed medication in the Western world, being a pivotal component in the primary and secondary prevention of cardiovascular (CV) diseases,” they wrote, but because randomized trials usually exclude patients with serious clinical conditions, the precise role statins play for frail patients, such as those with polypharmacy, “is still unclear.”
The population-based cohort study examined 29,047 Italian residents aged 65 years and older who were receiving uninterrupted treatment with statins as well as blood pressure–lowering, antidiabetic, and antiplatelet agents over 16 months. The follow-up period was more than 3 years.
The cohort members were followed to identify those for whom statins were discontinued. Those who continued taking other therapies during the first 6 months after stopping statins were propensity score matched in a 1:1 ratio with patients who did not discontinue taking statins or other drugs. The patient pairs were then followed for fatal and nonfatal outcomes to estimate the risk associated with statin discontinuation.
Of the overall cohort exposed to polypharmacy, 5819 (20.0%) discontinued statins while continuing to take their other medications. Of those, 4,010 were matched with a comparator.
Compared with the maintaining group, those who discontinued statins had the following outcomes: an increased risk for hospital admissions for heart failure (hazard ratio, 1.24; 95% confidence interval, 1.07-1.43), any cardiovascular outcomes (HR, 1.14; 95% CI, 1.03-1.26), death from any cause (HR, 1.15; 95% CI, 1.02-1.30), and emergency admissions for any cause (HR, 1.12; 95% CI, 1.01-1.19)
The increased risk occurred in patients with mild or severe profiles, regardless of gender and whether statins were prescribed as primary or secondary CV prevention.
“We expected that the discontinuation of statins could reduce the risk of access to the emergency department for neurological causes, considered a proxy for the onset of episodes of delirium, [but] this was not observed, suggesting that statin therapy has essential benefits on the reduction of fatal/nonfatal cardiovascular events with no harm effect,” said Dr. Rea, “at least considering major adverse events like hospital and emergency department admissions.”
Findings no surprise
Neil Stone, MD, Bonow Professor of Medicine (Cardiology) and Preventive Medicine at Northwestern University, Chicago, said the study results aren’t surprising.
“Older patients have a higher absolute risk of dying, and withdrawing proven therapy shown to reduce risk of coronary/stroke events in randomized, controlled trials would be expected to result in more cardiovascular events,” Dr. Stone said.
Although polypharmacy is a concern for the elderly and is a factor in decreased adherence, he said better solutions are needed than withdrawing proven, effective therapy. “In that sense, this study indirectly supports more research in the use of polypills to address cardiovascular risk factors,” he said. Giving a single pill that combines medications of proven value in reducing blood pressure and cholesterol might be preferable to reducing the total number of medications.
Given the complexity of polypharmacy, the study investigators say more attention is needed from all health care professionals who care for elderly patients.
“We hope that future studies can shed light on the best way to balance the undeniable benefit of [statins] and the harms, especially among the elderly exposed to polypharmacy,” said Rea.
Further research is also needed into why statins are discontinued in the first place, added Dr. Stone. “We know that statins often are stopped due to symptoms that on further scrutiny may not be related to statin use.”
The study was funded by grants from Fondo d’Ateneo per la Ricerca and Modelling Effectiveness, Cost-effectiveness, and Promoting Health Care Value in the Real World: the Motive Project from the Italian Ministry of the Education, University, and Research. One coauthor served on the advisory board of Roche and has received grants from Bristol Myers Squibb, GlaxoSmithKline, and Novartis outside the submitted work. The other authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Deprescribing may help in reducing inappropriate medication use and adverse events, but for cardiovascular care in the elderly, eliminating statins among patients taking other medications may have negative effects that far outweigh the benefits, a new study suggests.
In a large cohort study, researchers found that the withdrawal of statins from an elderly population receiving polypharmacy was associated with an increase in the risk for hospital admission for heart failure and any cardiovascular outcome, as well as death from any cause.
Statins are “lifesaving” drugs, and “according to the findings of our study, the discontinuation of this therapy has significant effects,” lead study author Federico Rea, PhD, research fellow, Laboratory of Healthcare Research and Pharmacoepidemiology, the department of statistics and quantitative methods, the University of Milano-Bicocca, said in an interview.
The article was published online June 14, 2021, in JAMA Network Open.
Negative clinical consequences, including adverse drug reactions leading to hospitalizations, are causing more physicians to consider deprescribing as a way to reduce problems associated with polypharmacy, the researchers noted.
Statins are “the most widely prescribed medication in the Western world, being a pivotal component in the primary and secondary prevention of cardiovascular (CV) diseases,” they wrote, but because randomized trials usually exclude patients with serious clinical conditions, the precise role statins play for frail patients, such as those with polypharmacy, “is still unclear.”
The population-based cohort study examined 29,047 Italian residents aged 65 years and older who were receiving uninterrupted treatment with statins as well as blood pressure–lowering, antidiabetic, and antiplatelet agents over 16 months. The follow-up period was more than 3 years.
The cohort members were followed to identify those for whom statins were discontinued. Those who continued taking other therapies during the first 6 months after stopping statins were propensity score matched in a 1:1 ratio with patients who did not discontinue taking statins or other drugs. The patient pairs were then followed for fatal and nonfatal outcomes to estimate the risk associated with statin discontinuation.
Of the overall cohort exposed to polypharmacy, 5819 (20.0%) discontinued statins while continuing to take their other medications. Of those, 4,010 were matched with a comparator.
Compared with the maintaining group, those who discontinued statins had the following outcomes: an increased risk for hospital admissions for heart failure (hazard ratio, 1.24; 95% confidence interval, 1.07-1.43), any cardiovascular outcomes (HR, 1.14; 95% CI, 1.03-1.26), death from any cause (HR, 1.15; 95% CI, 1.02-1.30), and emergency admissions for any cause (HR, 1.12; 95% CI, 1.01-1.19)
The increased risk occurred in patients with mild or severe profiles, regardless of gender and whether statins were prescribed as primary or secondary CV prevention.
“We expected that the discontinuation of statins could reduce the risk of access to the emergency department for neurological causes, considered a proxy for the onset of episodes of delirium, [but] this was not observed, suggesting that statin therapy has essential benefits on the reduction of fatal/nonfatal cardiovascular events with no harm effect,” said Dr. Rea, “at least considering major adverse events like hospital and emergency department admissions.”
Findings no surprise
Neil Stone, MD, Bonow Professor of Medicine (Cardiology) and Preventive Medicine at Northwestern University, Chicago, said the study results aren’t surprising.
“Older patients have a higher absolute risk of dying, and withdrawing proven therapy shown to reduce risk of coronary/stroke events in randomized, controlled trials would be expected to result in more cardiovascular events,” Dr. Stone said.
Although polypharmacy is a concern for the elderly and is a factor in decreased adherence, he said better solutions are needed than withdrawing proven, effective therapy. “In that sense, this study indirectly supports more research in the use of polypills to address cardiovascular risk factors,” he said. Giving a single pill that combines medications of proven value in reducing blood pressure and cholesterol might be preferable to reducing the total number of medications.
Given the complexity of polypharmacy, the study investigators say more attention is needed from all health care professionals who care for elderly patients.
“We hope that future studies can shed light on the best way to balance the undeniable benefit of [statins] and the harms, especially among the elderly exposed to polypharmacy,” said Rea.
Further research is also needed into why statins are discontinued in the first place, added Dr. Stone. “We know that statins often are stopped due to symptoms that on further scrutiny may not be related to statin use.”
The study was funded by grants from Fondo d’Ateneo per la Ricerca and Modelling Effectiveness, Cost-effectiveness, and Promoting Health Care Value in the Real World: the Motive Project from the Italian Ministry of the Education, University, and Research. One coauthor served on the advisory board of Roche and has received grants from Bristol Myers Squibb, GlaxoSmithKline, and Novartis outside the submitted work. The other authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Deprescribing may help in reducing inappropriate medication use and adverse events, but for cardiovascular care in the elderly, eliminating statins among patients taking other medications may have negative effects that far outweigh the benefits, a new study suggests.
In a large cohort study, researchers found that the withdrawal of statins from an elderly population receiving polypharmacy was associated with an increase in the risk for hospital admission for heart failure and any cardiovascular outcome, as well as death from any cause.
Statins are “lifesaving” drugs, and “according to the findings of our study, the discontinuation of this therapy has significant effects,” lead study author Federico Rea, PhD, research fellow, Laboratory of Healthcare Research and Pharmacoepidemiology, the department of statistics and quantitative methods, the University of Milano-Bicocca, said in an interview.
The article was published online June 14, 2021, in JAMA Network Open.
Negative clinical consequences, including adverse drug reactions leading to hospitalizations, are causing more physicians to consider deprescribing as a way to reduce problems associated with polypharmacy, the researchers noted.
Statins are “the most widely prescribed medication in the Western world, being a pivotal component in the primary and secondary prevention of cardiovascular (CV) diseases,” they wrote, but because randomized trials usually exclude patients with serious clinical conditions, the precise role statins play for frail patients, such as those with polypharmacy, “is still unclear.”
The population-based cohort study examined 29,047 Italian residents aged 65 years and older who were receiving uninterrupted treatment with statins as well as blood pressure–lowering, antidiabetic, and antiplatelet agents over 16 months. The follow-up period was more than 3 years.
The cohort members were followed to identify those for whom statins were discontinued. Those who continued taking other therapies during the first 6 months after stopping statins were propensity score matched in a 1:1 ratio with patients who did not discontinue taking statins or other drugs. The patient pairs were then followed for fatal and nonfatal outcomes to estimate the risk associated with statin discontinuation.
Of the overall cohort exposed to polypharmacy, 5819 (20.0%) discontinued statins while continuing to take their other medications. Of those, 4,010 were matched with a comparator.
Compared with the maintaining group, those who discontinued statins had the following outcomes: an increased risk for hospital admissions for heart failure (hazard ratio, 1.24; 95% confidence interval, 1.07-1.43), any cardiovascular outcomes (HR, 1.14; 95% CI, 1.03-1.26), death from any cause (HR, 1.15; 95% CI, 1.02-1.30), and emergency admissions for any cause (HR, 1.12; 95% CI, 1.01-1.19)
The increased risk occurred in patients with mild or severe profiles, regardless of gender and whether statins were prescribed as primary or secondary CV prevention.
“We expected that the discontinuation of statins could reduce the risk of access to the emergency department for neurological causes, considered a proxy for the onset of episodes of delirium, [but] this was not observed, suggesting that statin therapy has essential benefits on the reduction of fatal/nonfatal cardiovascular events with no harm effect,” said Dr. Rea, “at least considering major adverse events like hospital and emergency department admissions.”
Findings no surprise
Neil Stone, MD, Bonow Professor of Medicine (Cardiology) and Preventive Medicine at Northwestern University, Chicago, said the study results aren’t surprising.
“Older patients have a higher absolute risk of dying, and withdrawing proven therapy shown to reduce risk of coronary/stroke events in randomized, controlled trials would be expected to result in more cardiovascular events,” Dr. Stone said.
Although polypharmacy is a concern for the elderly and is a factor in decreased adherence, he said better solutions are needed than withdrawing proven, effective therapy. “In that sense, this study indirectly supports more research in the use of polypills to address cardiovascular risk factors,” he said. Giving a single pill that combines medications of proven value in reducing blood pressure and cholesterol might be preferable to reducing the total number of medications.
Given the complexity of polypharmacy, the study investigators say more attention is needed from all health care professionals who care for elderly patients.
“We hope that future studies can shed light on the best way to balance the undeniable benefit of [statins] and the harms, especially among the elderly exposed to polypharmacy,” said Rea.
Further research is also needed into why statins are discontinued in the first place, added Dr. Stone. “We know that statins often are stopped due to symptoms that on further scrutiny may not be related to statin use.”
The study was funded by grants from Fondo d’Ateneo per la Ricerca and Modelling Effectiveness, Cost-effectiveness, and Promoting Health Care Value in the Real World: the Motive Project from the Italian Ministry of the Education, University, and Research. One coauthor served on the advisory board of Roche and has received grants from Bristol Myers Squibb, GlaxoSmithKline, and Novartis outside the submitted work. The other authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Memory benefit seen with antihypertensives crossing blood-brain barrier
Over a 3-year period, cognitively normal older adults taking BBB-crossing antihypertensives demonstrated superior verbal memory, compared with similar individuals receiving non–BBB-crossing antihypertensives, reported lead author Jean K. Ho, PhD, of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, and colleagues.
According to the investigators, the findings add color to a known link between hypertension and neurologic degeneration, and may aid the search for new therapeutic targets.
“Hypertension is a well-established risk factor for cognitive decline and dementia, possibly through its effects on both cerebrovascular disease and Alzheimer’s disease,” Dr. Ho and colleagues wrote in Hypertension. “Studies of antihypertensive treatments have reported possible salutary effects on cognition and cerebrovascular disease, as well as Alzheimer’s disease neuropathology.”
In a previous study, individuals younger than 75 years exposed to antihypertensives had an 8% decreased risk of dementia per year of use, while another trial showed that intensive blood pressure–lowering therapy reduced mild cognitive impairment by 19%.
“Despite these encouraging findings ... larger meta-analytic studies have been hampered by the fact that pharmacokinetic properties are typically not considered in existing studies or routine clinical practice,” wrote Dr. Ho and colleagues. “The present study sought to fill this gap [in that it was] a large and longitudinal meta-analytic study of existing data recoded to assess the effects of BBB-crossing potential in renin-angiotensin system [RAS] treatments among hypertensive adults.”
Methods and results
The meta-analysis included randomized clinical trials, prospective cohort studies, and retrospective observational studies. The researchers assessed data on 12,849 individuals from 14 cohorts that received either BBB-crossing or non–BBB-crossing antihypertensives.
The BBB-crossing properties of RAS treatments were identified by a literature review. Of ACE inhibitors, captopril, fosinopril, lisinopril, perindopril, ramipril, and trandolapril were classified as BBB crossing, and benazepril, enalapril, moexipril, and quinapril were classified as non–BBB-crossing. Of ARBs, telmisartan and candesartan were considered BBB-crossing, and olmesartan, eprosartan, irbesartan, and losartan were tagged as non–BBB-crossing.
Cognition was assessed via the following seven domains: executive function, attention, verbal memory learning, language, mental status, recall, and processing speed.
Compared with individuals taking non–BBB-crossing antihypertensives, those taking BBB-crossing agents had significantly superior verbal memory (recall), with a maximum effect size of 0.07 (P = .03).
According to the investigators, this finding was particularly noteworthy, as the BBB-crossing group had relatively higher vascular risk burden and lower mean education level.
“These differences make it all the more remarkable that the BBB-crossing group displayed better memory ability over time despite these cognitive disadvantages,” the investigators wrote.
Still, not all the findings favored BBB-crossing agents. Individuals in the BBB-crossing group had relatively inferior attention ability, with a minimum effect size of –0.17 (P = .02).
The other cognitive measures were not significantly different between groups.
Clinicians may consider findings after accounting for other factors
Principal investigator Daniel A. Nation, PhD, associate professor of psychological science and a faculty member of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, suggested that the small difference in verbal memory between groups could be clinically significant over a longer period of time.
“Although the overall effect size was pretty small, if you look at how long it would take for someone [with dementia] to progress over many years of decline, it would actually end up being a pretty big effect,” Dr. Nation said in an interview. “Small effect sizes could actually end up preventing a lot of cases of dementia,” he added.
The conflicting results in the BBB-crossing group – better verbal memory but worse attention ability – were “surprising,” he noted.
“I sort of didn’t believe it at first,” Dr. Nation said, “because the memory finding is sort of replication – we’d observed the same exact effect on memory in a smaller sample in another study. ... The attention [finding], going another way, was a new thing.”
Dr. Nation suggested that the intergroup differences in attention ability may stem from idiosyncrasies of the tests used to measure that domain, which can be impacted by cardiovascular or brain vascular disease. Or it could be caused by something else entirely, he said, noting that further investigation is needed.
He added that the improvements in verbal memory within the BBB-crossing group could be caused by direct effects on the brain. He pointed out that certain ACE polymorphisms have been linked with Alzheimer’s disease risk, and those same polymorphisms, in animal models, lead to neurodegeneration, with reversal possible through administration of ACE inhibitors.
“It could be that what we’re observing has nothing really to do with blood pressure,” Dr. Nation explained. “This could be a neuronal effect on learning memory systems.”
He went on to suggest that clinicians may consider these findings when selecting antihypertensive agents for their patients, with the caveat that all other prescribing factors have already been taking to account.
“In the event that you’re going to give an ACE inhibitor or an angiotensin receptor blocker anyway, and it ends up being a somewhat arbitrary decision in terms of which specific drug you’re going to give, then perhaps this is a piece of information you would take into account – that one gets in the brain and one doesn’t – in somebody at risk for cognitive decline,” Dr. Nation said.
Exact mechanisms of action unknown
Hélène Girouard, PhD, assistant professor of pharmacology and physiology at the University of Montreal, said in an interview that the findings are “of considerable importance, knowing that brain alterations could begin as much as 30 years before manifestation of dementia.”
Since 2003, Dr. Girouard has been studying the cognitive effects of antihypertensive medications. She noted that previous studies involving rodents “have shown beneficial effects [of BBB-crossing antihypertensive drugs] on cognition independent of their effects on blood pressure.”
The drugs’ exact mechanisms of action, however, remain elusive, according to Dr. Girouard, who offered several possible explanations, including amelioration of BBB disruption, brain inflammation, cerebral blood flow dysregulation, cholinergic dysfunction, and neurologic deficits. “Whether these mechanisms may explain Ho and colleagues’ observations remains to be established,” she added.
Andrea L. Schneider, MD, PhD, assistant professor of neurology at the University of Pennsylvania, Philadelphia, applauded the study, but ultimately suggested that more research is needed to impact clinical decision-making.
“The results of this important and well-done study suggest that further investigation into targeted mechanism-based approaches to selecting hypertension treatment agents, with a specific focus on cognitive outcomes, is warranted,” Dr. Schneider said in an interview. “Before changing clinical practice, further work is necessary to disentangle contributions of medication mechanism, comorbid vascular risk factors, and achieved blood pressure reduction, among others.”
The investigators disclosed support from the National Institutes of Health, the Alzheimer’s Association, the Waksman Foundation of Japan, and others. The interviewees reported no relevant conflicts of interest.
Over a 3-year period, cognitively normal older adults taking BBB-crossing antihypertensives demonstrated superior verbal memory, compared with similar individuals receiving non–BBB-crossing antihypertensives, reported lead author Jean K. Ho, PhD, of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, and colleagues.
According to the investigators, the findings add color to a known link between hypertension and neurologic degeneration, and may aid the search for new therapeutic targets.
“Hypertension is a well-established risk factor for cognitive decline and dementia, possibly through its effects on both cerebrovascular disease and Alzheimer’s disease,” Dr. Ho and colleagues wrote in Hypertension. “Studies of antihypertensive treatments have reported possible salutary effects on cognition and cerebrovascular disease, as well as Alzheimer’s disease neuropathology.”
In a previous study, individuals younger than 75 years exposed to antihypertensives had an 8% decreased risk of dementia per year of use, while another trial showed that intensive blood pressure–lowering therapy reduced mild cognitive impairment by 19%.
“Despite these encouraging findings ... larger meta-analytic studies have been hampered by the fact that pharmacokinetic properties are typically not considered in existing studies or routine clinical practice,” wrote Dr. Ho and colleagues. “The present study sought to fill this gap [in that it was] a large and longitudinal meta-analytic study of existing data recoded to assess the effects of BBB-crossing potential in renin-angiotensin system [RAS] treatments among hypertensive adults.”
Methods and results
The meta-analysis included randomized clinical trials, prospective cohort studies, and retrospective observational studies. The researchers assessed data on 12,849 individuals from 14 cohorts that received either BBB-crossing or non–BBB-crossing antihypertensives.
The BBB-crossing properties of RAS treatments were identified by a literature review. Of ACE inhibitors, captopril, fosinopril, lisinopril, perindopril, ramipril, and trandolapril were classified as BBB crossing, and benazepril, enalapril, moexipril, and quinapril were classified as non–BBB-crossing. Of ARBs, telmisartan and candesartan were considered BBB-crossing, and olmesartan, eprosartan, irbesartan, and losartan were tagged as non–BBB-crossing.
Cognition was assessed via the following seven domains: executive function, attention, verbal memory learning, language, mental status, recall, and processing speed.
Compared with individuals taking non–BBB-crossing antihypertensives, those taking BBB-crossing agents had significantly superior verbal memory (recall), with a maximum effect size of 0.07 (P = .03).
According to the investigators, this finding was particularly noteworthy, as the BBB-crossing group had relatively higher vascular risk burden and lower mean education level.
“These differences make it all the more remarkable that the BBB-crossing group displayed better memory ability over time despite these cognitive disadvantages,” the investigators wrote.
Still, not all the findings favored BBB-crossing agents. Individuals in the BBB-crossing group had relatively inferior attention ability, with a minimum effect size of –0.17 (P = .02).
The other cognitive measures were not significantly different between groups.
Clinicians may consider findings after accounting for other factors
Principal investigator Daniel A. Nation, PhD, associate professor of psychological science and a faculty member of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, suggested that the small difference in verbal memory between groups could be clinically significant over a longer period of time.
“Although the overall effect size was pretty small, if you look at how long it would take for someone [with dementia] to progress over many years of decline, it would actually end up being a pretty big effect,” Dr. Nation said in an interview. “Small effect sizes could actually end up preventing a lot of cases of dementia,” he added.
The conflicting results in the BBB-crossing group – better verbal memory but worse attention ability – were “surprising,” he noted.
“I sort of didn’t believe it at first,” Dr. Nation said, “because the memory finding is sort of replication – we’d observed the same exact effect on memory in a smaller sample in another study. ... The attention [finding], going another way, was a new thing.”
Dr. Nation suggested that the intergroup differences in attention ability may stem from idiosyncrasies of the tests used to measure that domain, which can be impacted by cardiovascular or brain vascular disease. Or it could be caused by something else entirely, he said, noting that further investigation is needed.
He added that the improvements in verbal memory within the BBB-crossing group could be caused by direct effects on the brain. He pointed out that certain ACE polymorphisms have been linked with Alzheimer’s disease risk, and those same polymorphisms, in animal models, lead to neurodegeneration, with reversal possible through administration of ACE inhibitors.
“It could be that what we’re observing has nothing really to do with blood pressure,” Dr. Nation explained. “This could be a neuronal effect on learning memory systems.”
He went on to suggest that clinicians may consider these findings when selecting antihypertensive agents for their patients, with the caveat that all other prescribing factors have already been taking to account.
“In the event that you’re going to give an ACE inhibitor or an angiotensin receptor blocker anyway, and it ends up being a somewhat arbitrary decision in terms of which specific drug you’re going to give, then perhaps this is a piece of information you would take into account – that one gets in the brain and one doesn’t – in somebody at risk for cognitive decline,” Dr. Nation said.
Exact mechanisms of action unknown
Hélène Girouard, PhD, assistant professor of pharmacology and physiology at the University of Montreal, said in an interview that the findings are “of considerable importance, knowing that brain alterations could begin as much as 30 years before manifestation of dementia.”
Since 2003, Dr. Girouard has been studying the cognitive effects of antihypertensive medications. She noted that previous studies involving rodents “have shown beneficial effects [of BBB-crossing antihypertensive drugs] on cognition independent of their effects on blood pressure.”
The drugs’ exact mechanisms of action, however, remain elusive, according to Dr. Girouard, who offered several possible explanations, including amelioration of BBB disruption, brain inflammation, cerebral blood flow dysregulation, cholinergic dysfunction, and neurologic deficits. “Whether these mechanisms may explain Ho and colleagues’ observations remains to be established,” she added.
Andrea L. Schneider, MD, PhD, assistant professor of neurology at the University of Pennsylvania, Philadelphia, applauded the study, but ultimately suggested that more research is needed to impact clinical decision-making.
“The results of this important and well-done study suggest that further investigation into targeted mechanism-based approaches to selecting hypertension treatment agents, with a specific focus on cognitive outcomes, is warranted,” Dr. Schneider said in an interview. “Before changing clinical practice, further work is necessary to disentangle contributions of medication mechanism, comorbid vascular risk factors, and achieved blood pressure reduction, among others.”
The investigators disclosed support from the National Institutes of Health, the Alzheimer’s Association, the Waksman Foundation of Japan, and others. The interviewees reported no relevant conflicts of interest.
Over a 3-year period, cognitively normal older adults taking BBB-crossing antihypertensives demonstrated superior verbal memory, compared with similar individuals receiving non–BBB-crossing antihypertensives, reported lead author Jean K. Ho, PhD, of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, and colleagues.
According to the investigators, the findings add color to a known link between hypertension and neurologic degeneration, and may aid the search for new therapeutic targets.
“Hypertension is a well-established risk factor for cognitive decline and dementia, possibly through its effects on both cerebrovascular disease and Alzheimer’s disease,” Dr. Ho and colleagues wrote in Hypertension. “Studies of antihypertensive treatments have reported possible salutary effects on cognition and cerebrovascular disease, as well as Alzheimer’s disease neuropathology.”
In a previous study, individuals younger than 75 years exposed to antihypertensives had an 8% decreased risk of dementia per year of use, while another trial showed that intensive blood pressure–lowering therapy reduced mild cognitive impairment by 19%.
“Despite these encouraging findings ... larger meta-analytic studies have been hampered by the fact that pharmacokinetic properties are typically not considered in existing studies or routine clinical practice,” wrote Dr. Ho and colleagues. “The present study sought to fill this gap [in that it was] a large and longitudinal meta-analytic study of existing data recoded to assess the effects of BBB-crossing potential in renin-angiotensin system [RAS] treatments among hypertensive adults.”
Methods and results
The meta-analysis included randomized clinical trials, prospective cohort studies, and retrospective observational studies. The researchers assessed data on 12,849 individuals from 14 cohorts that received either BBB-crossing or non–BBB-crossing antihypertensives.
The BBB-crossing properties of RAS treatments were identified by a literature review. Of ACE inhibitors, captopril, fosinopril, lisinopril, perindopril, ramipril, and trandolapril were classified as BBB crossing, and benazepril, enalapril, moexipril, and quinapril were classified as non–BBB-crossing. Of ARBs, telmisartan and candesartan were considered BBB-crossing, and olmesartan, eprosartan, irbesartan, and losartan were tagged as non–BBB-crossing.
Cognition was assessed via the following seven domains: executive function, attention, verbal memory learning, language, mental status, recall, and processing speed.
Compared with individuals taking non–BBB-crossing antihypertensives, those taking BBB-crossing agents had significantly superior verbal memory (recall), with a maximum effect size of 0.07 (P = .03).
According to the investigators, this finding was particularly noteworthy, as the BBB-crossing group had relatively higher vascular risk burden and lower mean education level.
“These differences make it all the more remarkable that the BBB-crossing group displayed better memory ability over time despite these cognitive disadvantages,” the investigators wrote.
Still, not all the findings favored BBB-crossing agents. Individuals in the BBB-crossing group had relatively inferior attention ability, with a minimum effect size of –0.17 (P = .02).
The other cognitive measures were not significantly different between groups.
Clinicians may consider findings after accounting for other factors
Principal investigator Daniel A. Nation, PhD, associate professor of psychological science and a faculty member of the Institute for Memory Impairments and Neurological Disorders at the University of California, Irvine, suggested that the small difference in verbal memory between groups could be clinically significant over a longer period of time.
“Although the overall effect size was pretty small, if you look at how long it would take for someone [with dementia] to progress over many years of decline, it would actually end up being a pretty big effect,” Dr. Nation said in an interview. “Small effect sizes could actually end up preventing a lot of cases of dementia,” he added.
The conflicting results in the BBB-crossing group – better verbal memory but worse attention ability – were “surprising,” he noted.
“I sort of didn’t believe it at first,” Dr. Nation said, “because the memory finding is sort of replication – we’d observed the same exact effect on memory in a smaller sample in another study. ... The attention [finding], going another way, was a new thing.”
Dr. Nation suggested that the intergroup differences in attention ability may stem from idiosyncrasies of the tests used to measure that domain, which can be impacted by cardiovascular or brain vascular disease. Or it could be caused by something else entirely, he said, noting that further investigation is needed.
He added that the improvements in verbal memory within the BBB-crossing group could be caused by direct effects on the brain. He pointed out that certain ACE polymorphisms have been linked with Alzheimer’s disease risk, and those same polymorphisms, in animal models, lead to neurodegeneration, with reversal possible through administration of ACE inhibitors.
“It could be that what we’re observing has nothing really to do with blood pressure,” Dr. Nation explained. “This could be a neuronal effect on learning memory systems.”
He went on to suggest that clinicians may consider these findings when selecting antihypertensive agents for their patients, with the caveat that all other prescribing factors have already been taking to account.
“In the event that you’re going to give an ACE inhibitor or an angiotensin receptor blocker anyway, and it ends up being a somewhat arbitrary decision in terms of which specific drug you’re going to give, then perhaps this is a piece of information you would take into account – that one gets in the brain and one doesn’t – in somebody at risk for cognitive decline,” Dr. Nation said.
Exact mechanisms of action unknown
Hélène Girouard, PhD, assistant professor of pharmacology and physiology at the University of Montreal, said in an interview that the findings are “of considerable importance, knowing that brain alterations could begin as much as 30 years before manifestation of dementia.”
Since 2003, Dr. Girouard has been studying the cognitive effects of antihypertensive medications. She noted that previous studies involving rodents “have shown beneficial effects [of BBB-crossing antihypertensive drugs] on cognition independent of their effects on blood pressure.”
The drugs’ exact mechanisms of action, however, remain elusive, according to Dr. Girouard, who offered several possible explanations, including amelioration of BBB disruption, brain inflammation, cerebral blood flow dysregulation, cholinergic dysfunction, and neurologic deficits. “Whether these mechanisms may explain Ho and colleagues’ observations remains to be established,” she added.
Andrea L. Schneider, MD, PhD, assistant professor of neurology at the University of Pennsylvania, Philadelphia, applauded the study, but ultimately suggested that more research is needed to impact clinical decision-making.
“The results of this important and well-done study suggest that further investigation into targeted mechanism-based approaches to selecting hypertension treatment agents, with a specific focus on cognitive outcomes, is warranted,” Dr. Schneider said in an interview. “Before changing clinical practice, further work is necessary to disentangle contributions of medication mechanism, comorbid vascular risk factors, and achieved blood pressure reduction, among others.”
The investigators disclosed support from the National Institutes of Health, the Alzheimer’s Association, the Waksman Foundation of Japan, and others. The interviewees reported no relevant conflicts of interest.
FROM HYPERTENSION
Osteoporosis management: Use a goal-oriented, individualized approach
Recommendations for care are evolving, with increasingly sophisticated screening and diagnostic tools and a broadening array of treatment options.
As the population of older adults rises, primary osteoporosis has become a problem of public health significance, resulting in more than 2 million fractures and $19 billion in related costs annually in the United States.1 Despite the availability of effective primary and secondary preventive measures, many older adults do not receive adequate information on bone health from their primary care provider.2 Initiation of osteoporosis treatment is low even among patients who have had an osteoporotic fracture: Fewer than one-quarter of older adults with hip fracture have begun taking osteoporosis medication within 12 months of hospital discharge.3
In this overview of osteoporosis care, we provide information on how to evaluate and manage older adults in primary care settings who are at risk of, or have been given a diagnosis of, primary osteoporosis. The guidance that we offer reflects the most recent updates and recommendations by relevant professional societies.1,4-7
The nature and scope of an urgent problem
Osteoporosis is a skeletal disorder characterized by low bone mass and deterioration of bone structure that causes bone fragility and increases the risk of fracture.8 Operationally, it is defined by the World Health Organization as a bone mineral density (BMD) score below 2.5 SD from the mean value for a young White woman (ie, T-score ≤ –2.5).9 Primary osteoporosis is age related and occurs mostly in postmenopausal women and older men, affecting 25% of women and 5% of men ≥ 65 years.10
An osteoporotic fracture is particularly devastating in an older adult because it can cause pain, reduced mobility, depression, and social isolation and can increase the risk of related mortality.1 The National Osteoporosis Foundation estimates that 20% of older adults who sustain a hip fracture die within 1 year due to complications of the fracture itself or surgical repair.1 Therefore, it is of paramount importance to identify patients who are at increased risk of fracture and intervene early.
Clinical manifestations
Osteoporosis does not have a primary presentation; rather, disease manifests clinically when a patient develops complications. Often, a fragility fracture is the first sign in an older person.11
A fracture is the most important complication of osteoporosis and can result from low-trauma injury or a fall from standing height—thus, the term “fragility fracture.” Osteoporotic fractures commonly involve the vertebra, hip, and wrist. Hip and extremity fractures can result in limited or lost mobility and depression. Vertebral fractures can be asymptomatic or result in kyphosis and loss of height. Fractures can give rise to pain.
Age and female sexare risk factors
TABLE 11,6,10 lists risk factors associated with osteoporosis. Age is the most important; prevalence of osteoporosis increases with age. Other nonmodifiable risk factors include female sex (the disease appears earlier in women who enter menopause prematurely), family history of osteoporosis, and race and ethnicity. Twenty percent of Asian and non-Hispanic White women > 50 years have osteoporosis.1 A study showed that Mexican Americans are at higher risk of osteoporosis than non-Hispanic Whites; non-Hispanic Blacks are least affected.10
Other risk factors include low body weight (< 127 lb) and a history of fractures after age 50. Behavioral risk factors include smoking, excessive alcohol intake (> 3 drinks/d), poor nutrition, and a sedentary lifestyle.1,6
Continue to: Who should be screened?...
Who should be screened?
Screening is generally performed with a clinical evaluation and a dual-energy x-ray absorptiometry (DXA) scan of BMD. Measurement of BMD is generally recommended for screening all women ≥ 65 years and those < 65 years whose 10-year risk of fracture is equivalent to that of a 65-year-old White woman (see “Assessment of fracture risk” later in the article). For men, the US Preventive Services Task Force recommends screening those with a prior fracture or a secondary risk factor for disease.5 However, the National Osteoporosis Foundation recommends screening all men ≥ 70 years and those 50 to 69 years whose risk profile shows heightened risk.1,4
DXA of the spine and hip is preferred; the distal one-third of the radius (termed “33% radius”) of the nondominant arm can be used when spine and hip BMD cannot be interpreted because of bone changes from the disease process or artifacts, or in certain diseases in which the wrist region shows the earliest change (eg, primary hyperparathyroidism).6,7
Clinical evaluation includes a detailed history, physical examination, laboratory screening, and assessment for risk of fracture.
❚ History. Explore the presence of risk factors, including fractures in adulthood, falls, medication use, alcohol and tobacco use, family history of osteoporosis, and chronic disease.6,7
❚ Physical exam. Assess height, including any loss (> 1.5 in) since the patient’s second or third decade of life; kyphosis; frailty; and balance and mobility problems.4,6,7
❚ Laboratory and imaging studies. Perform basic laboratory testing when DXA is abnormal, including thyroid function, serum calcium, and renal function.6,12 Radiography of the lateral spine might be necessary, especially when there is kyphosis or loss of height. Assess for vertebral fracture, using lateral spine radiography, when vertebral involvement is suspected.6,7
❚ Assessment of fracture risk. Fracture risk can be assessed with any of a number of tools, including:
- Simplified Calculated Osteoporosis Risk Estimation (SCORE): www.medicalalgorithms.com/simplified-calculated-osteoporosis-risk-estimation-tool
- Osteoporosis Risk Assessment Instrument (ORAI): www.physio-pedia.com/The_Osteoporosis_Risk_Assessment_Instrument_(ORAI)
- Osteoporosis Index of Risk (OSIRIS): https://www.tandfonline.com/doi/abs/10.1080/gye.16.3.245.250?journalCode=igye20
- Osteoporosis Self-Assessment Tool (OST): www.ncbi.nlm.nih.gov/books/NBK45516/figure/ch10.f2/
- FRAX tool5: www.sheffield.ac.uk/FRAX.
The FRAX tool is widely used. It assesses a patient’s 10-year risk of fracture.
Diagnosis is based on these criteria
Diagnosis of osteoporosis is based on any 1 or more of the following criteria6:
- a history of fragility fracture not explained by metabolic bone disease
- T-score ≤ –2.5 (lumbar, hip, femoral neck, or 33% radius)
- a nation-specific FRAX score (in the absence of access to DXA).
❚ Secondary disease. Patients in whom secondary osteoporosis is suspected should undergo laboratory investigation to ascertain the cause; treatment of the underlying pathology might then be required. Evaluation for a secondary cause might include a complete blood count, comprehensive metabolic panel, protein electrophoresis and urinary protein electrophoresis (to rule out myeloproliferative and hematologic diseases), and tests of serum 25-hydroxyvitamin D, parathyroid hormone, serum calcium, alkaline phosphatase, 24-hour urinary calcium, sodium, and creatinine.6,7 Specialized testing for biochemical markers of bone turnover—so-called bone-turnover markers—can be considered as part of the initial evaluation and follow-up, although the tests are not recommended by the US Preventive Services Task Force (see “Monitoring the efficacy of treatment,” later in the article, for more information about these markers).6
Although BMD by DXA remains the gold standard in screening for and diagnosing osteoporosis, a high rate of fracture is seen in patients with certain diseases, such as type 2 diabetes and ankylosing spondylitis, who have a nonosteoporotic low T-score. This raises concerns about the usefulness of BMD for diagnosing osteoporosis in patients who have one of these diseases.13-16
❚
❚ Trabecular bone score (TBS), a surrogate bone-quality measure that is calculated based on the spine DXA image, has recently been introduced in clinical practice, and can be used to predict fracture risk in conjunction with BMD assessment by DXA and the FRAX score.17 TBS provides an indirect index of the trabecular microarchitecture using pixel gray-level variation in lumbar spine DXA images.18 Three categories of TBS (≤ 1.200, degraded microarchitecture; 1.200-1.350, partially degraded microarchitecture; and > 1.350, normal microarchitecture) have been reported to correspond with a T-score of, respectively, ≤ −2.5; −2.5 to −1.0; and > −1.0.18 TBS can be used only in patients with a body mass index of 15 to 37.5.19,20
There is no recommendation for monitoring bone quality using TBS after osteoporosis treatment. Such monitoring is at the clinician’s discretion for appropriate patients who might not show a risk of fracture, based on BMD measurement.
Continue to: Putting preventive measures into practice...
Putting preventive measures into practice
Measures to prevent osteoporosis and preserve bone health (TABLE 21,6) are best started in childhood but can be initiated at any age and maintained through the lifespan. Encourage older adults to adopt dietary and behavioral strategies to improve their bone health and prevent fracture. We recommend the following strategies; take each patient’s individual situation into consideration when electing to adopt any of these measures.
❚ Vitamin D. Consider checking the serum 25-hydroxyvitamin D level and providing supplementation (800-1000 IU daily, the National Osteoporosis Foundation recommends1) as necessary to maintain the level at 30-50 ng/mL.6
❚ Calcium. Encourage a daily dietary calcium intake of 1000-1200 mg. Supplement calcium if you determine that diet does not provide an adequate amount.
❚ Alcohol. Advise patients to limit consumption to < 3 drinks a day.
❚ Tobacco. Advise smoking cessation.
❚ Activity. Encourage an active lifestyle, including regular weight-bearing and balance exercises and resistance exercises such as Pilates, weightlifting, and tai chi. The regimen should be tailored to the patient’s individual situation.
❚ Medical therapy for concomitant illness. When possible, prescribe medications for chronic comorbidities that can also benefit bone health. For example, long-term use of angiotensin-converting enzyme (ACE) inhibitors and thiazide diuretics for hypertension are associated with a slower decline in BMD in some populations.21-23
Tailor treatment to patient’s circumstances
TABLE 34,6,24 describes indications for pharmacotherapy in osteoporosis. Pharmacotherapy is recommended in all cases of osteoporosis and osteopenia when fracture risk is high.24
Generally, you should undertake a discussion with the patient of the relative risks and benefits of treatment, taking into account their values and preferences, to come to a shared decision. Tailoring treatment, based on the patient’s distinctive circumstances, through shared decision-making is key to compliance.25
Pharmacotherapy is not indicated in patients whose risk of fracture is low; however, you should reassess such patients every 2 to 4 years.26 Women with a very high BMD might not need to be retested with DXA any sooner than every 10 to 15 years.
There are 3 main classes of first-line pharmacotherapeutic agents for osteoporosis in older adults (TABLE 44,6,7,26-41): antiresorptives (bisphosphonates and denosumab), anabolics (teriparatide and abaloparatide), and a monoclonal sclerostin antibody (romosozumab). (TABLE 44,6,7,26-41 and the discussion in this section also remark on the selective estrogen-receptor modulator raloxifene, which is used in special clinical circumstances but has been removed from the first line of osteoporosis pharmacotherapy.)
❚ Bisphosphonates. Oral bisphosphonates (alendronate, ibandronate, risedronate) can be used as initial treatment in patients with a high risk of fracture.35 Bisphosphonates have been shown to reduce fracture risk and improve BMD. When an oral bisphosphonate cannot be tolerated, intravenous zoledronate or ibandronate can be used.41
Patients treated with a bisphosphonate should be assessed for their fracture risk after 3 to 5 years of treatment26; when intravenous zoledronate is given as initial therapy, patients should be assessed after 3 years. After assessment, patients who remain at high risk should continue treatment; those whose fracture risk has decreased to low or moderate should have treatment temporarily suspended (bisphosphonate holiday) for as long as 5 years.26 Patients on bisphosphonate holiday should have their fracture risk assessed at 2- to 4-year intervals.26 Restart treatment if there is an increase in fracture risk (eg, a decrease in BMD) or if a fracture occurs. Bisphosphonates have a prolonged effect on BMD—for many years after treatment is discontinued.27,28
Oral bisphosphonates are associated with gastroesophageal reflux disease, difficulty swallowing, and gastritis. Rare adverse effects include osteonecrosis of the jaw and atypical femur fracture.29
❚ Denosumab, a recombinant human antibody, is a relatively newer antiresorptive for initial treatment. Denosumab, 60 mg, is given subcutaneously every 6 months. The drug can be used when bisphosphonates are contraindicated, the patient finds the bisphosphonate dosing regimen difficult to follow, or the patient is unresponsive to bisphosphonates.
Patients taking denosumab are reassessed every 5 to 10 years to determine whether to continue therapy or change to a new drug. Abrupt discontinuation of therapy can lead to rebound bone loss and increased risk of fracture.30-32 As with bisphosphonates, long-term use can be associated with osteonecrosis of the jaw and atypical femur fracture.33
There is no recommendation for a drug holiday for denosumab. An increase in, or no loss of, bone density and no new fractures while being treated are signs of effective treatment. There is no guideline for stopping denosumab, unless the patient develops adverse effects.
❚ Bone anabolics. Patients with a very high risk of fracture (eg, who have sustained multiple vertebral fractures), can begin treatment with teriparatide (20 μg/d subcutaneously) or abaloparatide (80 μg/d subcutaneously) for as long as 2 years, followed by treatment with an antiresorptive, such as a bisphosphonate.4,6 Teriparatide can be used in patients who have not responded to an antiresorptive as first-line treatment.
Both abaloparatide and teriparatide might be associated with a risk of osteosarcoma and are contraindicated in patients who are at increased risk of osteosarcoma.36,39,40
❚ Romosozumab, a monoclonal sclerostin antibody, can be used in patients with very high risk of fracture or with multiple vertebral fractures. Romosozumab increases bone formation and reduces bone resorption. It is given monthly, 210 mg subcutaneously, for 1 year. The recommendation is that patients who have completed a course of romosozumab continue with antiresorptive treatment.26
Romosozumab is associated with an increase in the risk of cardiovascular disease, including stroke and myocardial infarction.26
❚ Raloxifene, a selective estrogen-receptor modulator, is no longer a first-line agent for osteoporosis in older adults34 because of its association with an increased risk of deep-vein thrombosis, pulmonary embolism, and lethal stroke. However, raloxifene can be used, at 60 mg/d, when bisphosphonates or denosumab are unsuitable. In addition, raloxifene is particularly useful in women with a high risk of breast cancer and in men who are taking a long-acting gonadotropin-releasing hormone agonist for prostate cancer.37,38
Continue to: Influence of chronic...
Influence of chronic diseaseon bone health
Chronic diseases—hypertension, type 2 diabetes, hyperthyroidism, rheumatoid arthritis, ankylosing spondylitis, and gastroenterologic disorders such as celiac disease and ulcerative colitis—are known to affect bone loss that can hasten osteoporosis.16,18,21 Furthermore, medications used to treat chronic diseases are known to affect bone health: Some, such as statins, ACE inhibitors, and hydrochlorothiazide, are bone protective; others, such as steroids, pioglitazone, and selective serotonin reuptake inhibitors, accelerate bone loss.1,14,42,43 It is important to be aware of the effect of a patient’s chronic diseases, and treatments for those diseases, on bone health, to help develop an individualized osteoporosis prevention plan.
Monitoring the efficacy of treatment
Treatment of osteoporosis should not be initiated without baseline measurement of BMD of the spine and hip. Subsequent to establishing that baseline, serial measurement of BMD can be used to (1) determine when treatment needs to be initiated for an untreated patient and (2) assess response in a treated patient. There is no consensus on the interval at which DXA should be repeated for the purpose of monitoring treatment response; frequency depends on the individual’s circumstances and the medication used. Notably, many physicians repeat DXA after 2 years of treatment8; however, the American College of Physicians recommends against repeating DXA within the first 5 years of pharmacotherapy in women.24
Patients with suspected vertebral fracture or those with loss of height > 1.5 inches require lateral radiographs of the thoracic and lumbar spine to assess the status of fractures.4,6
❚ Bone-turnover markers measured in serum can be used to assess treatment efficacy and patient adherence. The formation marker procollagen type I N-terminal propeptide (P1NP) and the resorption marker beta C-terminal cross-linking telopeptide of type 1 collagen (bCTX) are preferred for evaluating bone turnover in the clinical setting. Assessing P1NP and bCTX at baseline and after 3 months of treatment might be effective in monitoring adherence, particularly in patients taking a bisphosphonate.44
Be sure to address fall prevention
It is important to address falls, and how to prevent them, in patients with osteoporosis. Falls can precipitate fracture in older adults with reduced BMD, and fractures are the most common and debilitating manifestation of osteoporosis. Your discussion of falls with patients should include45:
- consequences of falls
- cautions about medications that can cloud mental alertness
- use of appropriate footwear
- home safety, such as adequate lighting, removal of floor clutter, and installation of handrails in the bathroom and stairwells and on outside steps.
- having an annual comprehensive eye exam.
Osteoporosis is avoidable and treatable
Earlier research reported various expressions of number needed to treat for medical management of osteoporosis—making it difficult to follow a single number as a reference for gauging the effectiveness of pharmacotherapy.46,47 However, for older adults of different ethnic and racial backgrounds with multiple comorbidities and polypharmacy, it might be more pragmatic in primary care to establish a model of goal-oriented, individualized care. By focusing on prevention of bone loss, and being mindful that the risk of fracture almost doubles with a decrease of 1 SD in BMD, you can translate numbers to goals of care.48
In the United States, approximately one-half of osteoporosis cases in adults ≥ 50 years are managed by primary care providers. As a chronic disease, osteoporosis requires that you, first, provide regular monitoring and assessment, because risk can vary with comorbidities,49 and, second, discuss and initiate screening and treatment as appropriate, which can be done annually during a well-care visit.
CORRESPONDENCE
Nahid Rianon, MD, DrPH, Department of Family and Community Medicine, UTHealth McGovern Medical School, 6431 Fannin Street #JJL 324C, Houston, TX, 77030; [email protected]
- What is osteoporosis and what causes it? National Osteoporosis Foundation Website. 2020. Accessed April 28, 2021. www.nof.org/patients/what-is-osteoporosis/
- des Bordes J, Prasad S, Pratt G, et al. Knowledge, beliefs, and concerns about bone health from a systematic review and metasynthesis of qualitative studies. PLoS One. 2020;15:e0227765. doi: 10.1371/journal.pone.0227765
- Solomon DH, Johnston SS, Boytsov NN, et al. Osteoporosis medication use after hip fracture in U.S. patients between 2002 and 2011. J Bone Miner Res. 2014;29:1929-1937. doi: 10.1002/jbmr.2202
- Cosman F, de Beur SJ, LeBoff MS, et al; National Osteoporosis Foundation. Clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25:2359-2381. doi: 10.1007/s00198-014-2794-2
- US Preventive Services Task Force; Curry SJ, Krist AH, Owens DK, et al. Screening for osteoporosis to prevent fractures: US Preventive Services Task Force recommendation statement. JAMA. 2018;319:2521-2531. doi: 10.1001/jama.2018.7498
- Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis - 2016. Endocr Pract. 2016;22(suppl 4):1-42. doi: 10.4158/EP161435.GL
- Watts NB, Adler RA, Bilezikian JP, et al; Endocrine Society. Osteoporosis in men: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2012;97:1802-1822. doi: 10.1210/jc.2011-3045
- US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. US Department of Health and Human Services, Public Health Service, Office of the Surgeon General; 2004. Accessed April 28, 2021. www.ncbi.nlm.nih.gov/books/NBK45513/pdf/Bookshelf_NBK45513.pdf
- Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser. 1994;843:1-129.
- Looker AC, Frenk SM. Percentage of adults aged 65 and over with osteoporosis or low bone mass at the femur neck or lumbar spine: United States, 2005--2010. Centers for Disease Control and Prevention, National Center for Health Statistics, Division of Health and Nutrition Examination Surveys. August 2015. Accessed April 28, 2021. www.cdc.gov/nchs/data/hestat/osteoporsis/osteoporosis2005_2010.pdf
- Kerschan-Schindl K. Prevention and rehabilitation of osteoporosis. Wien Med Wochenschr. 2016;166:22-27. doi: 10.1007/s10354-015-0417-y
- Tarantino U, Iolascon G, Cianferotti L, et al. Clinical guidelines for the prevention and treatment of osteoporosis: summary statements and recommendations from the Italian Society for Orthopaedics and Traumatology. J Orthop Traumatol. 2017;18(suppl 1):3-36. doi: 10.1007/s10195-017-0474-7
- Martineau P, Leslie WD, Johansson H, et al. In which patients does lumbar spine trabecular bone score (TBS) have the largest effect? Bone. 2018;113:161-168. doi: 10.1016/j.bone.2018.05.026
- Rianon NJ, Smith SM, Lee M, et al. Glycemic control and bone turnover in older Mexican Americans with type 2 diabetes. J Osteoporos. 2018;2018:7153021. doi: 10.1155/2018/7153021
- Richards C, Hans D, Leslie WD. Trabecular bone score (TBS) predicts fracture in ankylosing spondylitis: The Manitoba BMD Registry. J Clin Densitom. 2020;23:543-548. doi: 10.1016/j.jocd.2020.01.003
- Xue Y, Baker AL, Nader S, et al. Lumbar spine trabecular bone score (TBS) reflects diminished bone quality in patients with diabetes mellitus and oral glucocorticoid therapy. J Clin Densitom. 2018;21:185-192. doi: 10.1016/j.jocd.2017.09.003
- Silva BC, Broy SB, Boutroy S, et al. Fracture risk prediction by non-BMD DXA measures: the 2015 ISCD Official Positions Part 2: trabecular bone score. J Clin Densitom. 2015;18:309-330. doi: 10.1016/j.jocd.2015.06.008
- Silva BC, Leslie WD, Resch H, et al. Trabecular bone score: a noninvasive analytical method based upon the DXA image. J Bone Miner Res. 2014;29:518-530. doi: 10.1002/jbmr.2176
- Leslie WD, Aubry-Rozier B, Lamy O, et al; Manitoba Bone Density Program. TBS (trabecular bone score) and diabetes-related fracture risk. J Clin Endocrinol Metab. 2013;98:602-609.
- Looker AC, Sarafrazi Isfahani N, Fan B, et al. Trabecular bone scores and lumbar spine bone mineral density of US adults: comparison of relationships with demographic and body size variables. Osteoporos Int. 2016;27:2467-2475. doi: 10.1007/s00198-016-3550-6
- Rianon N, Ambrose CG, Pervin H, et al. Long-term use of angiotensin-converting enzyme inhibitors protects against bone loss in African-American elderly men. Arch Osteoporos. 2017;12:94. doi: 10.1007/s11657-017-0387-3
- Morton DJ, Barrett-Connor EL, Edelstein SL. Thiazides and bone mineral density in elderly men and women. Am J Epidemiol. 1994;139:1107-1115. doi: 10.1093/oxfordjournals.aje.a116954
- Sigurdsson G, Franzson L. Increased bone mineral density in a population-based group of 70-year-old women on thiazide diuretics, independent of parathyroid hormone levels. J Intern Med. 2001;250:51-56. doi: 10.1046/j.1365-2796.2001.00850.x
- Qaseem A, Forciea MA, McLean RM, et al; Clinical Guidelines Committee of the American College of Physicians. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166:818-839. doi: 10.7326/M15-1361
- des Bordes JKA, Suarez-Almazor ME, Volk RJ, et al. Online educational tool to promote bone health in cancer survivors. J Health Commun. 2017;22:808-817. doi: 10.1080/10810730.2017.1360415
- Shoback D, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society guideline update. J Clin Endocrinol Metab. 2020;105:587-594. doi: 10.1210/clinem/dgaa048
- Black DM, Schwartz AV, Ensrud KE, et al; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927-2938. doi: 10.1001/jama.296.24.2927
- Bone HG, Hosking D, Devogelaer J-P, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189-1199. doi: 10.1056/NEJMoa030897
- Khosla S, Burr D, Cauley J, et al; American Society for Bone and Mineral Research. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479-1491. doi: 10.1359/jbmr.0707onj
- Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96:972-980. doi: 10.1210/jc.2010-1502
- Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM Trial and its extension. J Bone Miner Res. 2018;33:190-198. doi: 10.1002/jbmr.3337
- Symonds C, Kline G. Warning of an increased risk of vertebral fracture after stopping denosumab. CMAJ. 2018;190:E485-E486. doi: 10.1503/cmaj.180115
- Aljohani S, Gaudin R, Weiser J, et al. Osteonecrosis of the jaw in patients treated with denosumab: a multicenter case series. J Craniomaxillofac Surg. 2018;46:1515-1525. doi: 10.1016/j.jcms.2018.05.046
- Barrett-Connor E, Mosca L, Collins P, et al; Raloxifene Use for The Heart (RUTH) Trial Investigators. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125-137. doi: 10.1056/NEJMoa062462
- Chesnut CH 3rd, Skag A, Christiansen C, et al; Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE). Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241-1249. doi: 10.1359/JBMR.040325
- Gilsenban A, Midkiff K, Kellier-Steele N, et al. Teriparatide did not increase adult osteosarcoma incidence in a 15-year US postmarketing surveillance study. J Bone Miner Res. 2021;36:244-252. doi: 10.1002/jbmr.4188
- Cuzick J, Sestak I, Bonanni B, et al; SERM Chemoprevention of Breast Cancer Overview Group. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet. 2013;381:1827-1834. doi: 10.1016/S0140-6736(13)60140-3
- Smith MR, Fallon MA, Lee H, et al. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89:3841-3846. doi: 10.1210/jc.2003-032058
- TYMLOS. Prescribing information. Radius Health, Inc.; April 2017. Accessed May 20, 2021. www.accessdata.fda.gov/drugsatfda_docs/label/2017/208743lbl.pdf
- FORTEO. Prescribing information. Eli Lilly and Co.; April 2020. Accessed May 20, 2021. www.accessdata.fda.gov/drugsatfda_docs/label/2020/021318s053lbl.pdf
- Wooltorton E. Patients receiving intravenous bisphosphonates should avoid invasive dental procedures. Can Med Assoc J. 2003;172:1684. doi: https://doi.org/10.1503/cmaj.050640
- Chiadika SM, Shobayo FO, Naqvi SH, et al. Lower femoral neck bone mineral density (BMD) in elderly women not on statins. Women Health. 2019;59:845-853. doi: 10.1080/03630242.2019.1567646
- Saraykar S, John V, Cao B, et al. Association of selective serotonin reuptake inhibitors and bone mineral density in elderly women. J Clin Densitom. 2018;21:193-199. doi: 10.1016/j.jocd.2017.05.016
- Lorentzon M, Branco J, Brandi ML, et al. Algorithm for the use of biochemical markers of bone turnover in the diagnosis, assessment and follow-up of treatment for osteoporosis. Adv Ther. 2019;36:2811-2824. doi: 10.1007/s12325-019-01063-9
- STEADI--older adult fall prevention. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. 2019. Accessed April 28, 2021. www.cdc.gov/steadi/patient.html
- Cummings SR, San Martin J, McClung MR, et al; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-765. doi: 10.1056/NEJMoa0809493
- Zhou Z, Chen C, Zhang J, et al. Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis. Int J Clin Exp Pathol. 2014;7:2113-2122.
- Faulkner KG. Bone matters: are density increases necessary to reduce fracture risk? J Bone Miner Res. 2000;15:183-187. doi: 10.1359/jbmr.2000.15.2.183
- Rianon N, Anand D, Rasu R. Changing trends in osteoporosis care from specialty to primary care physicians. Curr Med Res Opin. 2013;29:881-888. doi: 10.1185/03007995.2013.809335
Recommendations for care are evolving, with increasingly sophisticated screening and diagnostic tools and a broadening array of treatment options.
Recommendations for care are evolving, with increasingly sophisticated screening and diagnostic tools and a broadening array of treatment options.
As the population of older adults rises, primary osteoporosis has become a problem of public health significance, resulting in more than 2 million fractures and $19 billion in related costs annually in the United States.1 Despite the availability of effective primary and secondary preventive measures, many older adults do not receive adequate information on bone health from their primary care provider.2 Initiation of osteoporosis treatment is low even among patients who have had an osteoporotic fracture: Fewer than one-quarter of older adults with hip fracture have begun taking osteoporosis medication within 12 months of hospital discharge.3
In this overview of osteoporosis care, we provide information on how to evaluate and manage older adults in primary care settings who are at risk of, or have been given a diagnosis of, primary osteoporosis. The guidance that we offer reflects the most recent updates and recommendations by relevant professional societies.1,4-7
The nature and scope of an urgent problem
Osteoporosis is a skeletal disorder characterized by low bone mass and deterioration of bone structure that causes bone fragility and increases the risk of fracture.8 Operationally, it is defined by the World Health Organization as a bone mineral density (BMD) score below 2.5 SD from the mean value for a young White woman (ie, T-score ≤ –2.5).9 Primary osteoporosis is age related and occurs mostly in postmenopausal women and older men, affecting 25% of women and 5% of men ≥ 65 years.10
An osteoporotic fracture is particularly devastating in an older adult because it can cause pain, reduced mobility, depression, and social isolation and can increase the risk of related mortality.1 The National Osteoporosis Foundation estimates that 20% of older adults who sustain a hip fracture die within 1 year due to complications of the fracture itself or surgical repair.1 Therefore, it is of paramount importance to identify patients who are at increased risk of fracture and intervene early.
Clinical manifestations
Osteoporosis does not have a primary presentation; rather, disease manifests clinically when a patient develops complications. Often, a fragility fracture is the first sign in an older person.11
A fracture is the most important complication of osteoporosis and can result from low-trauma injury or a fall from standing height—thus, the term “fragility fracture.” Osteoporotic fractures commonly involve the vertebra, hip, and wrist. Hip and extremity fractures can result in limited or lost mobility and depression. Vertebral fractures can be asymptomatic or result in kyphosis and loss of height. Fractures can give rise to pain.
Age and female sexare risk factors
TABLE 11,6,10 lists risk factors associated with osteoporosis. Age is the most important; prevalence of osteoporosis increases with age. Other nonmodifiable risk factors include female sex (the disease appears earlier in women who enter menopause prematurely), family history of osteoporosis, and race and ethnicity. Twenty percent of Asian and non-Hispanic White women > 50 years have osteoporosis.1 A study showed that Mexican Americans are at higher risk of osteoporosis than non-Hispanic Whites; non-Hispanic Blacks are least affected.10
Other risk factors include low body weight (< 127 lb) and a history of fractures after age 50. Behavioral risk factors include smoking, excessive alcohol intake (> 3 drinks/d), poor nutrition, and a sedentary lifestyle.1,6
Continue to: Who should be screened?...
Who should be screened?
Screening is generally performed with a clinical evaluation and a dual-energy x-ray absorptiometry (DXA) scan of BMD. Measurement of BMD is generally recommended for screening all women ≥ 65 years and those < 65 years whose 10-year risk of fracture is equivalent to that of a 65-year-old White woman (see “Assessment of fracture risk” later in the article). For men, the US Preventive Services Task Force recommends screening those with a prior fracture or a secondary risk factor for disease.5 However, the National Osteoporosis Foundation recommends screening all men ≥ 70 years and those 50 to 69 years whose risk profile shows heightened risk.1,4
DXA of the spine and hip is preferred; the distal one-third of the radius (termed “33% radius”) of the nondominant arm can be used when spine and hip BMD cannot be interpreted because of bone changes from the disease process or artifacts, or in certain diseases in which the wrist region shows the earliest change (eg, primary hyperparathyroidism).6,7
Clinical evaluation includes a detailed history, physical examination, laboratory screening, and assessment for risk of fracture.
❚ History. Explore the presence of risk factors, including fractures in adulthood, falls, medication use, alcohol and tobacco use, family history of osteoporosis, and chronic disease.6,7
❚ Physical exam. Assess height, including any loss (> 1.5 in) since the patient’s second or third decade of life; kyphosis; frailty; and balance and mobility problems.4,6,7
❚ Laboratory and imaging studies. Perform basic laboratory testing when DXA is abnormal, including thyroid function, serum calcium, and renal function.6,12 Radiography of the lateral spine might be necessary, especially when there is kyphosis or loss of height. Assess for vertebral fracture, using lateral spine radiography, when vertebral involvement is suspected.6,7
❚ Assessment of fracture risk. Fracture risk can be assessed with any of a number of tools, including:
- Simplified Calculated Osteoporosis Risk Estimation (SCORE): www.medicalalgorithms.com/simplified-calculated-osteoporosis-risk-estimation-tool
- Osteoporosis Risk Assessment Instrument (ORAI): www.physio-pedia.com/The_Osteoporosis_Risk_Assessment_Instrument_(ORAI)
- Osteoporosis Index of Risk (OSIRIS): https://www.tandfonline.com/doi/abs/10.1080/gye.16.3.245.250?journalCode=igye20
- Osteoporosis Self-Assessment Tool (OST): www.ncbi.nlm.nih.gov/books/NBK45516/figure/ch10.f2/
- FRAX tool5: www.sheffield.ac.uk/FRAX.
The FRAX tool is widely used. It assesses a patient’s 10-year risk of fracture.
Diagnosis is based on these criteria
Diagnosis of osteoporosis is based on any 1 or more of the following criteria6:
- a history of fragility fracture not explained by metabolic bone disease
- T-score ≤ –2.5 (lumbar, hip, femoral neck, or 33% radius)
- a nation-specific FRAX score (in the absence of access to DXA).
❚ Secondary disease. Patients in whom secondary osteoporosis is suspected should undergo laboratory investigation to ascertain the cause; treatment of the underlying pathology might then be required. Evaluation for a secondary cause might include a complete blood count, comprehensive metabolic panel, protein electrophoresis and urinary protein electrophoresis (to rule out myeloproliferative and hematologic diseases), and tests of serum 25-hydroxyvitamin D, parathyroid hormone, serum calcium, alkaline phosphatase, 24-hour urinary calcium, sodium, and creatinine.6,7 Specialized testing for biochemical markers of bone turnover—so-called bone-turnover markers—can be considered as part of the initial evaluation and follow-up, although the tests are not recommended by the US Preventive Services Task Force (see “Monitoring the efficacy of treatment,” later in the article, for more information about these markers).6
Although BMD by DXA remains the gold standard in screening for and diagnosing osteoporosis, a high rate of fracture is seen in patients with certain diseases, such as type 2 diabetes and ankylosing spondylitis, who have a nonosteoporotic low T-score. This raises concerns about the usefulness of BMD for diagnosing osteoporosis in patients who have one of these diseases.13-16
❚
❚ Trabecular bone score (TBS), a surrogate bone-quality measure that is calculated based on the spine DXA image, has recently been introduced in clinical practice, and can be used to predict fracture risk in conjunction with BMD assessment by DXA and the FRAX score.17 TBS provides an indirect index of the trabecular microarchitecture using pixel gray-level variation in lumbar spine DXA images.18 Three categories of TBS (≤ 1.200, degraded microarchitecture; 1.200-1.350, partially degraded microarchitecture; and > 1.350, normal microarchitecture) have been reported to correspond with a T-score of, respectively, ≤ −2.5; −2.5 to −1.0; and > −1.0.18 TBS can be used only in patients with a body mass index of 15 to 37.5.19,20
There is no recommendation for monitoring bone quality using TBS after osteoporosis treatment. Such monitoring is at the clinician’s discretion for appropriate patients who might not show a risk of fracture, based on BMD measurement.
Continue to: Putting preventive measures into practice...
Putting preventive measures into practice
Measures to prevent osteoporosis and preserve bone health (TABLE 21,6) are best started in childhood but can be initiated at any age and maintained through the lifespan. Encourage older adults to adopt dietary and behavioral strategies to improve their bone health and prevent fracture. We recommend the following strategies; take each patient’s individual situation into consideration when electing to adopt any of these measures.
❚ Vitamin D. Consider checking the serum 25-hydroxyvitamin D level and providing supplementation (800-1000 IU daily, the National Osteoporosis Foundation recommends1) as necessary to maintain the level at 30-50 ng/mL.6
❚ Calcium. Encourage a daily dietary calcium intake of 1000-1200 mg. Supplement calcium if you determine that diet does not provide an adequate amount.
❚ Alcohol. Advise patients to limit consumption to < 3 drinks a day.
❚ Tobacco. Advise smoking cessation.
❚ Activity. Encourage an active lifestyle, including regular weight-bearing and balance exercises and resistance exercises such as Pilates, weightlifting, and tai chi. The regimen should be tailored to the patient’s individual situation.
❚ Medical therapy for concomitant illness. When possible, prescribe medications for chronic comorbidities that can also benefit bone health. For example, long-term use of angiotensin-converting enzyme (ACE) inhibitors and thiazide diuretics for hypertension are associated with a slower decline in BMD in some populations.21-23
Tailor treatment to patient’s circumstances
TABLE 34,6,24 describes indications for pharmacotherapy in osteoporosis. Pharmacotherapy is recommended in all cases of osteoporosis and osteopenia when fracture risk is high.24
Generally, you should undertake a discussion with the patient of the relative risks and benefits of treatment, taking into account their values and preferences, to come to a shared decision. Tailoring treatment, based on the patient’s distinctive circumstances, through shared decision-making is key to compliance.25
Pharmacotherapy is not indicated in patients whose risk of fracture is low; however, you should reassess such patients every 2 to 4 years.26 Women with a very high BMD might not need to be retested with DXA any sooner than every 10 to 15 years.
There are 3 main classes of first-line pharmacotherapeutic agents for osteoporosis in older adults (TABLE 44,6,7,26-41): antiresorptives (bisphosphonates and denosumab), anabolics (teriparatide and abaloparatide), and a monoclonal sclerostin antibody (romosozumab). (TABLE 44,6,7,26-41 and the discussion in this section also remark on the selective estrogen-receptor modulator raloxifene, which is used in special clinical circumstances but has been removed from the first line of osteoporosis pharmacotherapy.)
❚ Bisphosphonates. Oral bisphosphonates (alendronate, ibandronate, risedronate) can be used as initial treatment in patients with a high risk of fracture.35 Bisphosphonates have been shown to reduce fracture risk and improve BMD. When an oral bisphosphonate cannot be tolerated, intravenous zoledronate or ibandronate can be used.41
Patients treated with a bisphosphonate should be assessed for their fracture risk after 3 to 5 years of treatment26; when intravenous zoledronate is given as initial therapy, patients should be assessed after 3 years. After assessment, patients who remain at high risk should continue treatment; those whose fracture risk has decreased to low or moderate should have treatment temporarily suspended (bisphosphonate holiday) for as long as 5 years.26 Patients on bisphosphonate holiday should have their fracture risk assessed at 2- to 4-year intervals.26 Restart treatment if there is an increase in fracture risk (eg, a decrease in BMD) or if a fracture occurs. Bisphosphonates have a prolonged effect on BMD—for many years after treatment is discontinued.27,28
Oral bisphosphonates are associated with gastroesophageal reflux disease, difficulty swallowing, and gastritis. Rare adverse effects include osteonecrosis of the jaw and atypical femur fracture.29
❚ Denosumab, a recombinant human antibody, is a relatively newer antiresorptive for initial treatment. Denosumab, 60 mg, is given subcutaneously every 6 months. The drug can be used when bisphosphonates are contraindicated, the patient finds the bisphosphonate dosing regimen difficult to follow, or the patient is unresponsive to bisphosphonates.
Patients taking denosumab are reassessed every 5 to 10 years to determine whether to continue therapy or change to a new drug. Abrupt discontinuation of therapy can lead to rebound bone loss and increased risk of fracture.30-32 As with bisphosphonates, long-term use can be associated with osteonecrosis of the jaw and atypical femur fracture.33
There is no recommendation for a drug holiday for denosumab. An increase in, or no loss of, bone density and no new fractures while being treated are signs of effective treatment. There is no guideline for stopping denosumab, unless the patient develops adverse effects.
❚ Bone anabolics. Patients with a very high risk of fracture (eg, who have sustained multiple vertebral fractures), can begin treatment with teriparatide (20 μg/d subcutaneously) or abaloparatide (80 μg/d subcutaneously) for as long as 2 years, followed by treatment with an antiresorptive, such as a bisphosphonate.4,6 Teriparatide can be used in patients who have not responded to an antiresorptive as first-line treatment.
Both abaloparatide and teriparatide might be associated with a risk of osteosarcoma and are contraindicated in patients who are at increased risk of osteosarcoma.36,39,40
❚ Romosozumab, a monoclonal sclerostin antibody, can be used in patients with very high risk of fracture or with multiple vertebral fractures. Romosozumab increases bone formation and reduces bone resorption. It is given monthly, 210 mg subcutaneously, for 1 year. The recommendation is that patients who have completed a course of romosozumab continue with antiresorptive treatment.26
Romosozumab is associated with an increase in the risk of cardiovascular disease, including stroke and myocardial infarction.26
❚ Raloxifene, a selective estrogen-receptor modulator, is no longer a first-line agent for osteoporosis in older adults34 because of its association with an increased risk of deep-vein thrombosis, pulmonary embolism, and lethal stroke. However, raloxifene can be used, at 60 mg/d, when bisphosphonates or denosumab are unsuitable. In addition, raloxifene is particularly useful in women with a high risk of breast cancer and in men who are taking a long-acting gonadotropin-releasing hormone agonist for prostate cancer.37,38
Continue to: Influence of chronic...
Influence of chronic diseaseon bone health
Chronic diseases—hypertension, type 2 diabetes, hyperthyroidism, rheumatoid arthritis, ankylosing spondylitis, and gastroenterologic disorders such as celiac disease and ulcerative colitis—are known to affect bone loss that can hasten osteoporosis.16,18,21 Furthermore, medications used to treat chronic diseases are known to affect bone health: Some, such as statins, ACE inhibitors, and hydrochlorothiazide, are bone protective; others, such as steroids, pioglitazone, and selective serotonin reuptake inhibitors, accelerate bone loss.1,14,42,43 It is important to be aware of the effect of a patient’s chronic diseases, and treatments for those diseases, on bone health, to help develop an individualized osteoporosis prevention plan.
Monitoring the efficacy of treatment
Treatment of osteoporosis should not be initiated without baseline measurement of BMD of the spine and hip. Subsequent to establishing that baseline, serial measurement of BMD can be used to (1) determine when treatment needs to be initiated for an untreated patient and (2) assess response in a treated patient. There is no consensus on the interval at which DXA should be repeated for the purpose of monitoring treatment response; frequency depends on the individual’s circumstances and the medication used. Notably, many physicians repeat DXA after 2 years of treatment8; however, the American College of Physicians recommends against repeating DXA within the first 5 years of pharmacotherapy in women.24
Patients with suspected vertebral fracture or those with loss of height > 1.5 inches require lateral radiographs of the thoracic and lumbar spine to assess the status of fractures.4,6
❚ Bone-turnover markers measured in serum can be used to assess treatment efficacy and patient adherence. The formation marker procollagen type I N-terminal propeptide (P1NP) and the resorption marker beta C-terminal cross-linking telopeptide of type 1 collagen (bCTX) are preferred for evaluating bone turnover in the clinical setting. Assessing P1NP and bCTX at baseline and after 3 months of treatment might be effective in monitoring adherence, particularly in patients taking a bisphosphonate.44
Be sure to address fall prevention
It is important to address falls, and how to prevent them, in patients with osteoporosis. Falls can precipitate fracture in older adults with reduced BMD, and fractures are the most common and debilitating manifestation of osteoporosis. Your discussion of falls with patients should include45:
- consequences of falls
- cautions about medications that can cloud mental alertness
- use of appropriate footwear
- home safety, such as adequate lighting, removal of floor clutter, and installation of handrails in the bathroom and stairwells and on outside steps.
- having an annual comprehensive eye exam.
Osteoporosis is avoidable and treatable
Earlier research reported various expressions of number needed to treat for medical management of osteoporosis—making it difficult to follow a single number as a reference for gauging the effectiveness of pharmacotherapy.46,47 However, for older adults of different ethnic and racial backgrounds with multiple comorbidities and polypharmacy, it might be more pragmatic in primary care to establish a model of goal-oriented, individualized care. By focusing on prevention of bone loss, and being mindful that the risk of fracture almost doubles with a decrease of 1 SD in BMD, you can translate numbers to goals of care.48
In the United States, approximately one-half of osteoporosis cases in adults ≥ 50 years are managed by primary care providers. As a chronic disease, osteoporosis requires that you, first, provide regular monitoring and assessment, because risk can vary with comorbidities,49 and, second, discuss and initiate screening and treatment as appropriate, which can be done annually during a well-care visit.
CORRESPONDENCE
Nahid Rianon, MD, DrPH, Department of Family and Community Medicine, UTHealth McGovern Medical School, 6431 Fannin Street #JJL 324C, Houston, TX, 77030; [email protected]
As the population of older adults rises, primary osteoporosis has become a problem of public health significance, resulting in more than 2 million fractures and $19 billion in related costs annually in the United States.1 Despite the availability of effective primary and secondary preventive measures, many older adults do not receive adequate information on bone health from their primary care provider.2 Initiation of osteoporosis treatment is low even among patients who have had an osteoporotic fracture: Fewer than one-quarter of older adults with hip fracture have begun taking osteoporosis medication within 12 months of hospital discharge.3
In this overview of osteoporosis care, we provide information on how to evaluate and manage older adults in primary care settings who are at risk of, or have been given a diagnosis of, primary osteoporosis. The guidance that we offer reflects the most recent updates and recommendations by relevant professional societies.1,4-7
The nature and scope of an urgent problem
Osteoporosis is a skeletal disorder characterized by low bone mass and deterioration of bone structure that causes bone fragility and increases the risk of fracture.8 Operationally, it is defined by the World Health Organization as a bone mineral density (BMD) score below 2.5 SD from the mean value for a young White woman (ie, T-score ≤ –2.5).9 Primary osteoporosis is age related and occurs mostly in postmenopausal women and older men, affecting 25% of women and 5% of men ≥ 65 years.10
An osteoporotic fracture is particularly devastating in an older adult because it can cause pain, reduced mobility, depression, and social isolation and can increase the risk of related mortality.1 The National Osteoporosis Foundation estimates that 20% of older adults who sustain a hip fracture die within 1 year due to complications of the fracture itself or surgical repair.1 Therefore, it is of paramount importance to identify patients who are at increased risk of fracture and intervene early.
Clinical manifestations
Osteoporosis does not have a primary presentation; rather, disease manifests clinically when a patient develops complications. Often, a fragility fracture is the first sign in an older person.11
A fracture is the most important complication of osteoporosis and can result from low-trauma injury or a fall from standing height—thus, the term “fragility fracture.” Osteoporotic fractures commonly involve the vertebra, hip, and wrist. Hip and extremity fractures can result in limited or lost mobility and depression. Vertebral fractures can be asymptomatic or result in kyphosis and loss of height. Fractures can give rise to pain.
Age and female sexare risk factors
TABLE 11,6,10 lists risk factors associated with osteoporosis. Age is the most important; prevalence of osteoporosis increases with age. Other nonmodifiable risk factors include female sex (the disease appears earlier in women who enter menopause prematurely), family history of osteoporosis, and race and ethnicity. Twenty percent of Asian and non-Hispanic White women > 50 years have osteoporosis.1 A study showed that Mexican Americans are at higher risk of osteoporosis than non-Hispanic Whites; non-Hispanic Blacks are least affected.10
Other risk factors include low body weight (< 127 lb) and a history of fractures after age 50. Behavioral risk factors include smoking, excessive alcohol intake (> 3 drinks/d), poor nutrition, and a sedentary lifestyle.1,6
Continue to: Who should be screened?...
Who should be screened?
Screening is generally performed with a clinical evaluation and a dual-energy x-ray absorptiometry (DXA) scan of BMD. Measurement of BMD is generally recommended for screening all women ≥ 65 years and those < 65 years whose 10-year risk of fracture is equivalent to that of a 65-year-old White woman (see “Assessment of fracture risk” later in the article). For men, the US Preventive Services Task Force recommends screening those with a prior fracture or a secondary risk factor for disease.5 However, the National Osteoporosis Foundation recommends screening all men ≥ 70 years and those 50 to 69 years whose risk profile shows heightened risk.1,4
DXA of the spine and hip is preferred; the distal one-third of the radius (termed “33% radius”) of the nondominant arm can be used when spine and hip BMD cannot be interpreted because of bone changes from the disease process or artifacts, or in certain diseases in which the wrist region shows the earliest change (eg, primary hyperparathyroidism).6,7
Clinical evaluation includes a detailed history, physical examination, laboratory screening, and assessment for risk of fracture.
❚ History. Explore the presence of risk factors, including fractures in adulthood, falls, medication use, alcohol and tobacco use, family history of osteoporosis, and chronic disease.6,7
❚ Physical exam. Assess height, including any loss (> 1.5 in) since the patient’s second or third decade of life; kyphosis; frailty; and balance and mobility problems.4,6,7
❚ Laboratory and imaging studies. Perform basic laboratory testing when DXA is abnormal, including thyroid function, serum calcium, and renal function.6,12 Radiography of the lateral spine might be necessary, especially when there is kyphosis or loss of height. Assess for vertebral fracture, using lateral spine radiography, when vertebral involvement is suspected.6,7
❚ Assessment of fracture risk. Fracture risk can be assessed with any of a number of tools, including:
- Simplified Calculated Osteoporosis Risk Estimation (SCORE): www.medicalalgorithms.com/simplified-calculated-osteoporosis-risk-estimation-tool
- Osteoporosis Risk Assessment Instrument (ORAI): www.physio-pedia.com/The_Osteoporosis_Risk_Assessment_Instrument_(ORAI)
- Osteoporosis Index of Risk (OSIRIS): https://www.tandfonline.com/doi/abs/10.1080/gye.16.3.245.250?journalCode=igye20
- Osteoporosis Self-Assessment Tool (OST): www.ncbi.nlm.nih.gov/books/NBK45516/figure/ch10.f2/
- FRAX tool5: www.sheffield.ac.uk/FRAX.
The FRAX tool is widely used. It assesses a patient’s 10-year risk of fracture.
Diagnosis is based on these criteria
Diagnosis of osteoporosis is based on any 1 or more of the following criteria6:
- a history of fragility fracture not explained by metabolic bone disease
- T-score ≤ –2.5 (lumbar, hip, femoral neck, or 33% radius)
- a nation-specific FRAX score (in the absence of access to DXA).
❚ Secondary disease. Patients in whom secondary osteoporosis is suspected should undergo laboratory investigation to ascertain the cause; treatment of the underlying pathology might then be required. Evaluation for a secondary cause might include a complete blood count, comprehensive metabolic panel, protein electrophoresis and urinary protein electrophoresis (to rule out myeloproliferative and hematologic diseases), and tests of serum 25-hydroxyvitamin D, parathyroid hormone, serum calcium, alkaline phosphatase, 24-hour urinary calcium, sodium, and creatinine.6,7 Specialized testing for biochemical markers of bone turnover—so-called bone-turnover markers—can be considered as part of the initial evaluation and follow-up, although the tests are not recommended by the US Preventive Services Task Force (see “Monitoring the efficacy of treatment,” later in the article, for more information about these markers).6
Although BMD by DXA remains the gold standard in screening for and diagnosing osteoporosis, a high rate of fracture is seen in patients with certain diseases, such as type 2 diabetes and ankylosing spondylitis, who have a nonosteoporotic low T-score. This raises concerns about the usefulness of BMD for diagnosing osteoporosis in patients who have one of these diseases.13-16
❚
❚ Trabecular bone score (TBS), a surrogate bone-quality measure that is calculated based on the spine DXA image, has recently been introduced in clinical practice, and can be used to predict fracture risk in conjunction with BMD assessment by DXA and the FRAX score.17 TBS provides an indirect index of the trabecular microarchitecture using pixel gray-level variation in lumbar spine DXA images.18 Three categories of TBS (≤ 1.200, degraded microarchitecture; 1.200-1.350, partially degraded microarchitecture; and > 1.350, normal microarchitecture) have been reported to correspond with a T-score of, respectively, ≤ −2.5; −2.5 to −1.0; and > −1.0.18 TBS can be used only in patients with a body mass index of 15 to 37.5.19,20
There is no recommendation for monitoring bone quality using TBS after osteoporosis treatment. Such monitoring is at the clinician’s discretion for appropriate patients who might not show a risk of fracture, based on BMD measurement.
Continue to: Putting preventive measures into practice...
Putting preventive measures into practice
Measures to prevent osteoporosis and preserve bone health (TABLE 21,6) are best started in childhood but can be initiated at any age and maintained through the lifespan. Encourage older adults to adopt dietary and behavioral strategies to improve their bone health and prevent fracture. We recommend the following strategies; take each patient’s individual situation into consideration when electing to adopt any of these measures.
❚ Vitamin D. Consider checking the serum 25-hydroxyvitamin D level and providing supplementation (800-1000 IU daily, the National Osteoporosis Foundation recommends1) as necessary to maintain the level at 30-50 ng/mL.6
❚ Calcium. Encourage a daily dietary calcium intake of 1000-1200 mg. Supplement calcium if you determine that diet does not provide an adequate amount.
❚ Alcohol. Advise patients to limit consumption to < 3 drinks a day.
❚ Tobacco. Advise smoking cessation.
❚ Activity. Encourage an active lifestyle, including regular weight-bearing and balance exercises and resistance exercises such as Pilates, weightlifting, and tai chi. The regimen should be tailored to the patient’s individual situation.
❚ Medical therapy for concomitant illness. When possible, prescribe medications for chronic comorbidities that can also benefit bone health. For example, long-term use of angiotensin-converting enzyme (ACE) inhibitors and thiazide diuretics for hypertension are associated with a slower decline in BMD in some populations.21-23
Tailor treatment to patient’s circumstances
TABLE 34,6,24 describes indications for pharmacotherapy in osteoporosis. Pharmacotherapy is recommended in all cases of osteoporosis and osteopenia when fracture risk is high.24
Generally, you should undertake a discussion with the patient of the relative risks and benefits of treatment, taking into account their values and preferences, to come to a shared decision. Tailoring treatment, based on the patient’s distinctive circumstances, through shared decision-making is key to compliance.25
Pharmacotherapy is not indicated in patients whose risk of fracture is low; however, you should reassess such patients every 2 to 4 years.26 Women with a very high BMD might not need to be retested with DXA any sooner than every 10 to 15 years.
There are 3 main classes of first-line pharmacotherapeutic agents for osteoporosis in older adults (TABLE 44,6,7,26-41): antiresorptives (bisphosphonates and denosumab), anabolics (teriparatide and abaloparatide), and a monoclonal sclerostin antibody (romosozumab). (TABLE 44,6,7,26-41 and the discussion in this section also remark on the selective estrogen-receptor modulator raloxifene, which is used in special clinical circumstances but has been removed from the first line of osteoporosis pharmacotherapy.)
❚ Bisphosphonates. Oral bisphosphonates (alendronate, ibandronate, risedronate) can be used as initial treatment in patients with a high risk of fracture.35 Bisphosphonates have been shown to reduce fracture risk and improve BMD. When an oral bisphosphonate cannot be tolerated, intravenous zoledronate or ibandronate can be used.41
Patients treated with a bisphosphonate should be assessed for their fracture risk after 3 to 5 years of treatment26; when intravenous zoledronate is given as initial therapy, patients should be assessed after 3 years. After assessment, patients who remain at high risk should continue treatment; those whose fracture risk has decreased to low or moderate should have treatment temporarily suspended (bisphosphonate holiday) for as long as 5 years.26 Patients on bisphosphonate holiday should have their fracture risk assessed at 2- to 4-year intervals.26 Restart treatment if there is an increase in fracture risk (eg, a decrease in BMD) or if a fracture occurs. Bisphosphonates have a prolonged effect on BMD—for many years after treatment is discontinued.27,28
Oral bisphosphonates are associated with gastroesophageal reflux disease, difficulty swallowing, and gastritis. Rare adverse effects include osteonecrosis of the jaw and atypical femur fracture.29
❚ Denosumab, a recombinant human antibody, is a relatively newer antiresorptive for initial treatment. Denosumab, 60 mg, is given subcutaneously every 6 months. The drug can be used when bisphosphonates are contraindicated, the patient finds the bisphosphonate dosing regimen difficult to follow, or the patient is unresponsive to bisphosphonates.
Patients taking denosumab are reassessed every 5 to 10 years to determine whether to continue therapy or change to a new drug. Abrupt discontinuation of therapy can lead to rebound bone loss and increased risk of fracture.30-32 As with bisphosphonates, long-term use can be associated with osteonecrosis of the jaw and atypical femur fracture.33
There is no recommendation for a drug holiday for denosumab. An increase in, or no loss of, bone density and no new fractures while being treated are signs of effective treatment. There is no guideline for stopping denosumab, unless the patient develops adverse effects.
❚ Bone anabolics. Patients with a very high risk of fracture (eg, who have sustained multiple vertebral fractures), can begin treatment with teriparatide (20 μg/d subcutaneously) or abaloparatide (80 μg/d subcutaneously) for as long as 2 years, followed by treatment with an antiresorptive, such as a bisphosphonate.4,6 Teriparatide can be used in patients who have not responded to an antiresorptive as first-line treatment.
Both abaloparatide and teriparatide might be associated with a risk of osteosarcoma and are contraindicated in patients who are at increased risk of osteosarcoma.36,39,40
❚ Romosozumab, a monoclonal sclerostin antibody, can be used in patients with very high risk of fracture or with multiple vertebral fractures. Romosozumab increases bone formation and reduces bone resorption. It is given monthly, 210 mg subcutaneously, for 1 year. The recommendation is that patients who have completed a course of romosozumab continue with antiresorptive treatment.26
Romosozumab is associated with an increase in the risk of cardiovascular disease, including stroke and myocardial infarction.26
❚ Raloxifene, a selective estrogen-receptor modulator, is no longer a first-line agent for osteoporosis in older adults34 because of its association with an increased risk of deep-vein thrombosis, pulmonary embolism, and lethal stroke. However, raloxifene can be used, at 60 mg/d, when bisphosphonates or denosumab are unsuitable. In addition, raloxifene is particularly useful in women with a high risk of breast cancer and in men who are taking a long-acting gonadotropin-releasing hormone agonist for prostate cancer.37,38
Continue to: Influence of chronic...
Influence of chronic diseaseon bone health
Chronic diseases—hypertension, type 2 diabetes, hyperthyroidism, rheumatoid arthritis, ankylosing spondylitis, and gastroenterologic disorders such as celiac disease and ulcerative colitis—are known to affect bone loss that can hasten osteoporosis.16,18,21 Furthermore, medications used to treat chronic diseases are known to affect bone health: Some, such as statins, ACE inhibitors, and hydrochlorothiazide, are bone protective; others, such as steroids, pioglitazone, and selective serotonin reuptake inhibitors, accelerate bone loss.1,14,42,43 It is important to be aware of the effect of a patient’s chronic diseases, and treatments for those diseases, on bone health, to help develop an individualized osteoporosis prevention plan.
Monitoring the efficacy of treatment
Treatment of osteoporosis should not be initiated without baseline measurement of BMD of the spine and hip. Subsequent to establishing that baseline, serial measurement of BMD can be used to (1) determine when treatment needs to be initiated for an untreated patient and (2) assess response in a treated patient. There is no consensus on the interval at which DXA should be repeated for the purpose of monitoring treatment response; frequency depends on the individual’s circumstances and the medication used. Notably, many physicians repeat DXA after 2 years of treatment8; however, the American College of Physicians recommends against repeating DXA within the first 5 years of pharmacotherapy in women.24
Patients with suspected vertebral fracture or those with loss of height > 1.5 inches require lateral radiographs of the thoracic and lumbar spine to assess the status of fractures.4,6
❚ Bone-turnover markers measured in serum can be used to assess treatment efficacy and patient adherence. The formation marker procollagen type I N-terminal propeptide (P1NP) and the resorption marker beta C-terminal cross-linking telopeptide of type 1 collagen (bCTX) are preferred for evaluating bone turnover in the clinical setting. Assessing P1NP and bCTX at baseline and after 3 months of treatment might be effective in monitoring adherence, particularly in patients taking a bisphosphonate.44
Be sure to address fall prevention
It is important to address falls, and how to prevent them, in patients with osteoporosis. Falls can precipitate fracture in older adults with reduced BMD, and fractures are the most common and debilitating manifestation of osteoporosis. Your discussion of falls with patients should include45:
- consequences of falls
- cautions about medications that can cloud mental alertness
- use of appropriate footwear
- home safety, such as adequate lighting, removal of floor clutter, and installation of handrails in the bathroom and stairwells and on outside steps.
- having an annual comprehensive eye exam.
Osteoporosis is avoidable and treatable
Earlier research reported various expressions of number needed to treat for medical management of osteoporosis—making it difficult to follow a single number as a reference for gauging the effectiveness of pharmacotherapy.46,47 However, for older adults of different ethnic and racial backgrounds with multiple comorbidities and polypharmacy, it might be more pragmatic in primary care to establish a model of goal-oriented, individualized care. By focusing on prevention of bone loss, and being mindful that the risk of fracture almost doubles with a decrease of 1 SD in BMD, you can translate numbers to goals of care.48
In the United States, approximately one-half of osteoporosis cases in adults ≥ 50 years are managed by primary care providers. As a chronic disease, osteoporosis requires that you, first, provide regular monitoring and assessment, because risk can vary with comorbidities,49 and, second, discuss and initiate screening and treatment as appropriate, which can be done annually during a well-care visit.
CORRESPONDENCE
Nahid Rianon, MD, DrPH, Department of Family and Community Medicine, UTHealth McGovern Medical School, 6431 Fannin Street #JJL 324C, Houston, TX, 77030; [email protected]
- What is osteoporosis and what causes it? National Osteoporosis Foundation Website. 2020. Accessed April 28, 2021. www.nof.org/patients/what-is-osteoporosis/
- des Bordes J, Prasad S, Pratt G, et al. Knowledge, beliefs, and concerns about bone health from a systematic review and metasynthesis of qualitative studies. PLoS One. 2020;15:e0227765. doi: 10.1371/journal.pone.0227765
- Solomon DH, Johnston SS, Boytsov NN, et al. Osteoporosis medication use after hip fracture in U.S. patients between 2002 and 2011. J Bone Miner Res. 2014;29:1929-1937. doi: 10.1002/jbmr.2202
- Cosman F, de Beur SJ, LeBoff MS, et al; National Osteoporosis Foundation. Clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25:2359-2381. doi: 10.1007/s00198-014-2794-2
- US Preventive Services Task Force; Curry SJ, Krist AH, Owens DK, et al. Screening for osteoporosis to prevent fractures: US Preventive Services Task Force recommendation statement. JAMA. 2018;319:2521-2531. doi: 10.1001/jama.2018.7498
- Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis - 2016. Endocr Pract. 2016;22(suppl 4):1-42. doi: 10.4158/EP161435.GL
- Watts NB, Adler RA, Bilezikian JP, et al; Endocrine Society. Osteoporosis in men: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2012;97:1802-1822. doi: 10.1210/jc.2011-3045
- US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. US Department of Health and Human Services, Public Health Service, Office of the Surgeon General; 2004. Accessed April 28, 2021. www.ncbi.nlm.nih.gov/books/NBK45513/pdf/Bookshelf_NBK45513.pdf
- Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser. 1994;843:1-129.
- Looker AC, Frenk SM. Percentage of adults aged 65 and over with osteoporosis or low bone mass at the femur neck or lumbar spine: United States, 2005--2010. Centers for Disease Control and Prevention, National Center for Health Statistics, Division of Health and Nutrition Examination Surveys. August 2015. Accessed April 28, 2021. www.cdc.gov/nchs/data/hestat/osteoporsis/osteoporosis2005_2010.pdf
- Kerschan-Schindl K. Prevention and rehabilitation of osteoporosis. Wien Med Wochenschr. 2016;166:22-27. doi: 10.1007/s10354-015-0417-y
- Tarantino U, Iolascon G, Cianferotti L, et al. Clinical guidelines for the prevention and treatment of osteoporosis: summary statements and recommendations from the Italian Society for Orthopaedics and Traumatology. J Orthop Traumatol. 2017;18(suppl 1):3-36. doi: 10.1007/s10195-017-0474-7
- Martineau P, Leslie WD, Johansson H, et al. In which patients does lumbar spine trabecular bone score (TBS) have the largest effect? Bone. 2018;113:161-168. doi: 10.1016/j.bone.2018.05.026
- Rianon NJ, Smith SM, Lee M, et al. Glycemic control and bone turnover in older Mexican Americans with type 2 diabetes. J Osteoporos. 2018;2018:7153021. doi: 10.1155/2018/7153021
- Richards C, Hans D, Leslie WD. Trabecular bone score (TBS) predicts fracture in ankylosing spondylitis: The Manitoba BMD Registry. J Clin Densitom. 2020;23:543-548. doi: 10.1016/j.jocd.2020.01.003
- Xue Y, Baker AL, Nader S, et al. Lumbar spine trabecular bone score (TBS) reflects diminished bone quality in patients with diabetes mellitus and oral glucocorticoid therapy. J Clin Densitom. 2018;21:185-192. doi: 10.1016/j.jocd.2017.09.003
- Silva BC, Broy SB, Boutroy S, et al. Fracture risk prediction by non-BMD DXA measures: the 2015 ISCD Official Positions Part 2: trabecular bone score. J Clin Densitom. 2015;18:309-330. doi: 10.1016/j.jocd.2015.06.008
- Silva BC, Leslie WD, Resch H, et al. Trabecular bone score: a noninvasive analytical method based upon the DXA image. J Bone Miner Res. 2014;29:518-530. doi: 10.1002/jbmr.2176
- Leslie WD, Aubry-Rozier B, Lamy O, et al; Manitoba Bone Density Program. TBS (trabecular bone score) and diabetes-related fracture risk. J Clin Endocrinol Metab. 2013;98:602-609.
- Looker AC, Sarafrazi Isfahani N, Fan B, et al. Trabecular bone scores and lumbar spine bone mineral density of US adults: comparison of relationships with demographic and body size variables. Osteoporos Int. 2016;27:2467-2475. doi: 10.1007/s00198-016-3550-6
- Rianon N, Ambrose CG, Pervin H, et al. Long-term use of angiotensin-converting enzyme inhibitors protects against bone loss in African-American elderly men. Arch Osteoporos. 2017;12:94. doi: 10.1007/s11657-017-0387-3
- Morton DJ, Barrett-Connor EL, Edelstein SL. Thiazides and bone mineral density in elderly men and women. Am J Epidemiol. 1994;139:1107-1115. doi: 10.1093/oxfordjournals.aje.a116954
- Sigurdsson G, Franzson L. Increased bone mineral density in a population-based group of 70-year-old women on thiazide diuretics, independent of parathyroid hormone levels. J Intern Med. 2001;250:51-56. doi: 10.1046/j.1365-2796.2001.00850.x
- Qaseem A, Forciea MA, McLean RM, et al; Clinical Guidelines Committee of the American College of Physicians. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166:818-839. doi: 10.7326/M15-1361
- des Bordes JKA, Suarez-Almazor ME, Volk RJ, et al. Online educational tool to promote bone health in cancer survivors. J Health Commun. 2017;22:808-817. doi: 10.1080/10810730.2017.1360415
- Shoback D, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society guideline update. J Clin Endocrinol Metab. 2020;105:587-594. doi: 10.1210/clinem/dgaa048
- Black DM, Schwartz AV, Ensrud KE, et al; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927-2938. doi: 10.1001/jama.296.24.2927
- Bone HG, Hosking D, Devogelaer J-P, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189-1199. doi: 10.1056/NEJMoa030897
- Khosla S, Burr D, Cauley J, et al; American Society for Bone and Mineral Research. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479-1491. doi: 10.1359/jbmr.0707onj
- Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96:972-980. doi: 10.1210/jc.2010-1502
- Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM Trial and its extension. J Bone Miner Res. 2018;33:190-198. doi: 10.1002/jbmr.3337
- Symonds C, Kline G. Warning of an increased risk of vertebral fracture after stopping denosumab. CMAJ. 2018;190:E485-E486. doi: 10.1503/cmaj.180115
- Aljohani S, Gaudin R, Weiser J, et al. Osteonecrosis of the jaw in patients treated with denosumab: a multicenter case series. J Craniomaxillofac Surg. 2018;46:1515-1525. doi: 10.1016/j.jcms.2018.05.046
- Barrett-Connor E, Mosca L, Collins P, et al; Raloxifene Use for The Heart (RUTH) Trial Investigators. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125-137. doi: 10.1056/NEJMoa062462
- Chesnut CH 3rd, Skag A, Christiansen C, et al; Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE). Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241-1249. doi: 10.1359/JBMR.040325
- Gilsenban A, Midkiff K, Kellier-Steele N, et al. Teriparatide did not increase adult osteosarcoma incidence in a 15-year US postmarketing surveillance study. J Bone Miner Res. 2021;36:244-252. doi: 10.1002/jbmr.4188
- Cuzick J, Sestak I, Bonanni B, et al; SERM Chemoprevention of Breast Cancer Overview Group. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet. 2013;381:1827-1834. doi: 10.1016/S0140-6736(13)60140-3
- Smith MR, Fallon MA, Lee H, et al. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89:3841-3846. doi: 10.1210/jc.2003-032058
- TYMLOS. Prescribing information. Radius Health, Inc.; April 2017. Accessed May 20, 2021. www.accessdata.fda.gov/drugsatfda_docs/label/2017/208743lbl.pdf
- FORTEO. Prescribing information. Eli Lilly and Co.; April 2020. Accessed May 20, 2021. www.accessdata.fda.gov/drugsatfda_docs/label/2020/021318s053lbl.pdf
- Wooltorton E. Patients receiving intravenous bisphosphonates should avoid invasive dental procedures. Can Med Assoc J. 2003;172:1684. doi: https://doi.org/10.1503/cmaj.050640
- Chiadika SM, Shobayo FO, Naqvi SH, et al. Lower femoral neck bone mineral density (BMD) in elderly women not on statins. Women Health. 2019;59:845-853. doi: 10.1080/03630242.2019.1567646
- Saraykar S, John V, Cao B, et al. Association of selective serotonin reuptake inhibitors and bone mineral density in elderly women. J Clin Densitom. 2018;21:193-199. doi: 10.1016/j.jocd.2017.05.016
- Lorentzon M, Branco J, Brandi ML, et al. Algorithm for the use of biochemical markers of bone turnover in the diagnosis, assessment and follow-up of treatment for osteoporosis. Adv Ther. 2019;36:2811-2824. doi: 10.1007/s12325-019-01063-9
- STEADI--older adult fall prevention. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. 2019. Accessed April 28, 2021. www.cdc.gov/steadi/patient.html
- Cummings SR, San Martin J, McClung MR, et al; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-765. doi: 10.1056/NEJMoa0809493
- Zhou Z, Chen C, Zhang J, et al. Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis. Int J Clin Exp Pathol. 2014;7:2113-2122.
- Faulkner KG. Bone matters: are density increases necessary to reduce fracture risk? J Bone Miner Res. 2000;15:183-187. doi: 10.1359/jbmr.2000.15.2.183
- Rianon N, Anand D, Rasu R. Changing trends in osteoporosis care from specialty to primary care physicians. Curr Med Res Opin. 2013;29:881-888. doi: 10.1185/03007995.2013.809335
- What is osteoporosis and what causes it? National Osteoporosis Foundation Website. 2020. Accessed April 28, 2021. www.nof.org/patients/what-is-osteoporosis/
- des Bordes J, Prasad S, Pratt G, et al. Knowledge, beliefs, and concerns about bone health from a systematic review and metasynthesis of qualitative studies. PLoS One. 2020;15:e0227765. doi: 10.1371/journal.pone.0227765
- Solomon DH, Johnston SS, Boytsov NN, et al. Osteoporosis medication use after hip fracture in U.S. patients between 2002 and 2011. J Bone Miner Res. 2014;29:1929-1937. doi: 10.1002/jbmr.2202
- Cosman F, de Beur SJ, LeBoff MS, et al; National Osteoporosis Foundation. Clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25:2359-2381. doi: 10.1007/s00198-014-2794-2
- US Preventive Services Task Force; Curry SJ, Krist AH, Owens DK, et al. Screening for osteoporosis to prevent fractures: US Preventive Services Task Force recommendation statement. JAMA. 2018;319:2521-2531. doi: 10.1001/jama.2018.7498
- Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis - 2016. Endocr Pract. 2016;22(suppl 4):1-42. doi: 10.4158/EP161435.GL
- Watts NB, Adler RA, Bilezikian JP, et al; Endocrine Society. Osteoporosis in men: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2012;97:1802-1822. doi: 10.1210/jc.2011-3045
- US Department of Health and Human Services. Bone Health and Osteoporosis: A Report of the Surgeon General. US Department of Health and Human Services, Public Health Service, Office of the Surgeon General; 2004. Accessed April 28, 2021. www.ncbi.nlm.nih.gov/books/NBK45513/pdf/Bookshelf_NBK45513.pdf
- Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. World Health Organ Tech Rep Ser. 1994;843:1-129.
- Looker AC, Frenk SM. Percentage of adults aged 65 and over with osteoporosis or low bone mass at the femur neck or lumbar spine: United States, 2005--2010. Centers for Disease Control and Prevention, National Center for Health Statistics, Division of Health and Nutrition Examination Surveys. August 2015. Accessed April 28, 2021. www.cdc.gov/nchs/data/hestat/osteoporsis/osteoporosis2005_2010.pdf
- Kerschan-Schindl K. Prevention and rehabilitation of osteoporosis. Wien Med Wochenschr. 2016;166:22-27. doi: 10.1007/s10354-015-0417-y
- Tarantino U, Iolascon G, Cianferotti L, et al. Clinical guidelines for the prevention and treatment of osteoporosis: summary statements and recommendations from the Italian Society for Orthopaedics and Traumatology. J Orthop Traumatol. 2017;18(suppl 1):3-36. doi: 10.1007/s10195-017-0474-7
- Martineau P, Leslie WD, Johansson H, et al. In which patients does lumbar spine trabecular bone score (TBS) have the largest effect? Bone. 2018;113:161-168. doi: 10.1016/j.bone.2018.05.026
- Rianon NJ, Smith SM, Lee M, et al. Glycemic control and bone turnover in older Mexican Americans with type 2 diabetes. J Osteoporos. 2018;2018:7153021. doi: 10.1155/2018/7153021
- Richards C, Hans D, Leslie WD. Trabecular bone score (TBS) predicts fracture in ankylosing spondylitis: The Manitoba BMD Registry. J Clin Densitom. 2020;23:543-548. doi: 10.1016/j.jocd.2020.01.003
- Xue Y, Baker AL, Nader S, et al. Lumbar spine trabecular bone score (TBS) reflects diminished bone quality in patients with diabetes mellitus and oral glucocorticoid therapy. J Clin Densitom. 2018;21:185-192. doi: 10.1016/j.jocd.2017.09.003
- Silva BC, Broy SB, Boutroy S, et al. Fracture risk prediction by non-BMD DXA measures: the 2015 ISCD Official Positions Part 2: trabecular bone score. J Clin Densitom. 2015;18:309-330. doi: 10.1016/j.jocd.2015.06.008
- Silva BC, Leslie WD, Resch H, et al. Trabecular bone score: a noninvasive analytical method based upon the DXA image. J Bone Miner Res. 2014;29:518-530. doi: 10.1002/jbmr.2176
- Leslie WD, Aubry-Rozier B, Lamy O, et al; Manitoba Bone Density Program. TBS (trabecular bone score) and diabetes-related fracture risk. J Clin Endocrinol Metab. 2013;98:602-609.
- Looker AC, Sarafrazi Isfahani N, Fan B, et al. Trabecular bone scores and lumbar spine bone mineral density of US adults: comparison of relationships with demographic and body size variables. Osteoporos Int. 2016;27:2467-2475. doi: 10.1007/s00198-016-3550-6
- Rianon N, Ambrose CG, Pervin H, et al. Long-term use of angiotensin-converting enzyme inhibitors protects against bone loss in African-American elderly men. Arch Osteoporos. 2017;12:94. doi: 10.1007/s11657-017-0387-3
- Morton DJ, Barrett-Connor EL, Edelstein SL. Thiazides and bone mineral density in elderly men and women. Am J Epidemiol. 1994;139:1107-1115. doi: 10.1093/oxfordjournals.aje.a116954
- Sigurdsson G, Franzson L. Increased bone mineral density in a population-based group of 70-year-old women on thiazide diuretics, independent of parathyroid hormone levels. J Intern Med. 2001;250:51-56. doi: 10.1046/j.1365-2796.2001.00850.x
- Qaseem A, Forciea MA, McLean RM, et al; Clinical Guidelines Committee of the American College of Physicians. Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 2017;166:818-839. doi: 10.7326/M15-1361
- des Bordes JKA, Suarez-Almazor ME, Volk RJ, et al. Online educational tool to promote bone health in cancer survivors. J Health Commun. 2017;22:808-817. doi: 10.1080/10810730.2017.1360415
- Shoback D, Rosen CJ, Black DM, et al. Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society guideline update. J Clin Endocrinol Metab. 2020;105:587-594. doi: 10.1210/clinem/dgaa048
- Black DM, Schwartz AV, Ensrud KE, et al; FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927-2938. doi: 10.1001/jama.296.24.2927
- Bone HG, Hosking D, Devogelaer J-P, et al. Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189-1199. doi: 10.1056/NEJMoa030897
- Khosla S, Burr D, Cauley J, et al; American Society for Bone and Mineral Research. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 2007;22:1479-1491. doi: 10.1359/jbmr.0707onj
- Bone HG, Bolognese MA, Yuen CK, et al. Effects of denosumab treatment and discontinuation on bone mineral density and bone turnover markers in postmenopausal women with low bone mass. J Clin Endocrinol Metab. 2011;96:972-980. doi: 10.1210/jc.2010-1502
- Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM Trial and its extension. J Bone Miner Res. 2018;33:190-198. doi: 10.1002/jbmr.3337
- Symonds C, Kline G. Warning of an increased risk of vertebral fracture after stopping denosumab. CMAJ. 2018;190:E485-E486. doi: 10.1503/cmaj.180115
- Aljohani S, Gaudin R, Weiser J, et al. Osteonecrosis of the jaw in patients treated with denosumab: a multicenter case series. J Craniomaxillofac Surg. 2018;46:1515-1525. doi: 10.1016/j.jcms.2018.05.046
- Barrett-Connor E, Mosca L, Collins P, et al; Raloxifene Use for The Heart (RUTH) Trial Investigators. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125-137. doi: 10.1056/NEJMoa062462
- Chesnut CH 3rd, Skag A, Christiansen C, et al; Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe (BONE). Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241-1249. doi: 10.1359/JBMR.040325
- Gilsenban A, Midkiff K, Kellier-Steele N, et al. Teriparatide did not increase adult osteosarcoma incidence in a 15-year US postmarketing surveillance study. J Bone Miner Res. 2021;36:244-252. doi: 10.1002/jbmr.4188
- Cuzick J, Sestak I, Bonanni B, et al; SERM Chemoprevention of Breast Cancer Overview Group. Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet. 2013;381:1827-1834. doi: 10.1016/S0140-6736(13)60140-3
- Smith MR, Fallon MA, Lee H, et al. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004;89:3841-3846. doi: 10.1210/jc.2003-032058
- TYMLOS. Prescribing information. Radius Health, Inc.; April 2017. Accessed May 20, 2021. www.accessdata.fda.gov/drugsatfda_docs/label/2017/208743lbl.pdf
- FORTEO. Prescribing information. Eli Lilly and Co.; April 2020. Accessed May 20, 2021. www.accessdata.fda.gov/drugsatfda_docs/label/2020/021318s053lbl.pdf
- Wooltorton E. Patients receiving intravenous bisphosphonates should avoid invasive dental procedures. Can Med Assoc J. 2003;172:1684. doi: https://doi.org/10.1503/cmaj.050640
- Chiadika SM, Shobayo FO, Naqvi SH, et al. Lower femoral neck bone mineral density (BMD) in elderly women not on statins. Women Health. 2019;59:845-853. doi: 10.1080/03630242.2019.1567646
- Saraykar S, John V, Cao B, et al. Association of selective serotonin reuptake inhibitors and bone mineral density in elderly women. J Clin Densitom. 2018;21:193-199. doi: 10.1016/j.jocd.2017.05.016
- Lorentzon M, Branco J, Brandi ML, et al. Algorithm for the use of biochemical markers of bone turnover in the diagnosis, assessment and follow-up of treatment for osteoporosis. Adv Ther. 2019;36:2811-2824. doi: 10.1007/s12325-019-01063-9
- STEADI--older adult fall prevention. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. 2019. Accessed April 28, 2021. www.cdc.gov/steadi/patient.html
- Cummings SR, San Martin J, McClung MR, et al; FREEDOM Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-765. doi: 10.1056/NEJMoa0809493
- Zhou Z, Chen C, Zhang J, et al. Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis. Int J Clin Exp Pathol. 2014;7:2113-2122.
- Faulkner KG. Bone matters: are density increases necessary to reduce fracture risk? J Bone Miner Res. 2000;15:183-187. doi: 10.1359/jbmr.2000.15.2.183
- Rianon N, Anand D, Rasu R. Changing trends in osteoporosis care from specialty to primary care physicians. Curr Med Res Opin. 2013;29:881-888. doi: 10.1185/03007995.2013.809335
PRACTICE RECOMMENDATIONS
❯ Consider screening for osteoporosis, using bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), in all postmenopausal women ≥ 65 years and in women < 65 years at high risk of osteoporosis.
❯ Consider screening in men ≥ 70 years and in younger men at high risk of fracture.
❯ Use the trabecular bone score with DXA BMD to screen patients at high risk of fracture who have a normal BMD—eg, patients with type 2 diabetes or ankylosing spondylitis.
❯ Offer individualized pharmacotherapy to older patients with a diagnosis of osteoporosis and to those at high risk of fracture.
Watchdog group demands removal of FDA leaders after aducanumab approval
In a letter to the U.S. Department of Health and Human Services Secretary Xavier Becerra, Michael A. Carome, MD, director of Public Citizen’s Health Research Group, said: “The FDA’s decision to approve aducanumab for anyone with Alzheimer’s disease, regardless of severity, showed a stunning disregard for science, eviscerated the agency’s standards for approving new drugs, and ranks as one of the most irresponsible and egregious decisions in the history of the agency.”
Public Citizen urged Mr. Becerra to seek the resignations or the removal of the three FDA officials it said were most responsible for the approval – Acting FDA Commissioner Janet Woodcock, MD; Center for Drug Evaluation and Research (CDER) Director Patrizia Cavazzoni, MD; and CDER’s Office of Neuroscience Director Billy Dunn, MD.
“This decision is a disastrous blow to the agency’s credibility, public health, and the financial sustainability of the Medicare program,” writes Dr. Carome, noting that Biogen said it would charge $56,000 annually for the infusion.
Aaron Kesselheim, MD, one of three FDA Peripheral and Central Nervous System Drugs advisory committee members who resigned in the wake of the approval, agreed with Public Citizen that the agency’s credibility is suffering.
“The aducanumab decision is the worst example yet of the FDA’s movement away from its high standards,” Dr. Kesselheim, a professor of medicine at Harvard Medical School, Boston, and Harvard colleague Jerry Avorn, MD, wrote in the New York Times on June 15.
“As physicians, we know well that Alzheimer’s disease is a terrible condition,” they wrote. However, they added, “approving a drug that has such poor evidence that it works and causes such worrisome side effects is not the solution.”
In his resignation letter, Dr. Kesselheim said he had also been dismayed by the agency’s 2016 approval of eteplirsen (Exondys 51, Sarepta Therapeutics) for Duchenne muscular dystrophy. In both the eteplirsen and aducanumab approvals, the agency went against its advisers’ recommendations, Dr. Kesselheim said.
Advocates who backed approval decry cost
Aducanumab had a rocky road to approval but had unwavering backing from the Alzheimer’s Association and at least one other organization, UsAgainstAlzheimer’s.
The Alzheimer’s Association was particularly outspoken in its support and, in March, was accused of potential conflict of interest by Public Citizen and several neurologists because the association accepted at least $1.4 million from Biogen and its partner Eisai since fiscal year 2018.
The association applauded the FDA approval but, a few days later, expressed outrage over the $56,000-a-year price tag.
“This price is simply unacceptable,” the Alzheimer’s Association said in the statement. “For many, this price will pose an insurmountable barrier to access, it complicates and jeopardizes sustainable access to this treatment, and may further deepen issues of health equity,” the association said, adding, “We call on Biogen to change this price.”
UsAgainstAlzheimer’s also expressed concerns about access, even before it knew aducanumab’s price.
“Shockingly, Medicare does not reimburse patients for the expensive PET scans important to determine whether someone is appropriate for this drug,” noted George Vradenburg, chairman and cofounder of the group, in a June 7 statement. “We intend to work with Biogen and Medicare to make access to this drug affordable for every American who needs it,” Mr. Vradenburg said.
Dr. Carome said the advocates’ complaints were hard to fathom.
“This should not have come as a surprise to anyone,” Dr. Carome said, adding that “it’s essentially the ballpark figure the company threw out weeks ago.”
“Fifty-six-thousand-dollars is particularly egregiously overpriced for a drug that doesn’t work,” Dr. Carome said. “If the [Alzheimer’s Association] truly finds this objectionable, hopefully they’ll stop accepting money from Biogen and its partner Eisai,” he added.
“The Alzheimer’s Association is recognizing that the genie is out of the bottle and that they are going to have trouble reining in the inevitable run-away costs,” said Mike Greicius, MD, MPH, associate professor of neurology at Stanford University’s Wu Tsai Neurosciences Institute, Stanford, California.
“In addition to the eye-popping annual cost that Biogen has invented, I hope the Alzheimer’s Association is also concerned about the dangerously loose and broad FDA labeling which does not require screening for amyloid-positivity and does not restrict use to the milder forms of disease studied in the Phase 3 trials,” Dr. Greicius said.
Another advocacy group, Patients For Affordable Drugs, commended the Alzheimer’s Association. Its statement “was nothing short of courageous, especially in light of the Alzheimer’s Association’s reliance on funding from drug corporations, including Biogen,” said David Mitchell, a cancer patient and founder of Patients For Affordable Drugs, in a statement.
Mr. Mitchell said his members “stand with the Alzheimer’s Association in its denunciation of the price set by Biogen” and called for a new law that would allow Medicare to negotiate drug prices.
A version of this article first appeared on Medscape.com.
In a letter to the U.S. Department of Health and Human Services Secretary Xavier Becerra, Michael A. Carome, MD, director of Public Citizen’s Health Research Group, said: “The FDA’s decision to approve aducanumab for anyone with Alzheimer’s disease, regardless of severity, showed a stunning disregard for science, eviscerated the agency’s standards for approving new drugs, and ranks as one of the most irresponsible and egregious decisions in the history of the agency.”
Public Citizen urged Mr. Becerra to seek the resignations or the removal of the three FDA officials it said were most responsible for the approval – Acting FDA Commissioner Janet Woodcock, MD; Center for Drug Evaluation and Research (CDER) Director Patrizia Cavazzoni, MD; and CDER’s Office of Neuroscience Director Billy Dunn, MD.
“This decision is a disastrous blow to the agency’s credibility, public health, and the financial sustainability of the Medicare program,” writes Dr. Carome, noting that Biogen said it would charge $56,000 annually for the infusion.
Aaron Kesselheim, MD, one of three FDA Peripheral and Central Nervous System Drugs advisory committee members who resigned in the wake of the approval, agreed with Public Citizen that the agency’s credibility is suffering.
“The aducanumab decision is the worst example yet of the FDA’s movement away from its high standards,” Dr. Kesselheim, a professor of medicine at Harvard Medical School, Boston, and Harvard colleague Jerry Avorn, MD, wrote in the New York Times on June 15.
“As physicians, we know well that Alzheimer’s disease is a terrible condition,” they wrote. However, they added, “approving a drug that has such poor evidence that it works and causes such worrisome side effects is not the solution.”
In his resignation letter, Dr. Kesselheim said he had also been dismayed by the agency’s 2016 approval of eteplirsen (Exondys 51, Sarepta Therapeutics) for Duchenne muscular dystrophy. In both the eteplirsen and aducanumab approvals, the agency went against its advisers’ recommendations, Dr. Kesselheim said.
Advocates who backed approval decry cost
Aducanumab had a rocky road to approval but had unwavering backing from the Alzheimer’s Association and at least one other organization, UsAgainstAlzheimer’s.
The Alzheimer’s Association was particularly outspoken in its support and, in March, was accused of potential conflict of interest by Public Citizen and several neurologists because the association accepted at least $1.4 million from Biogen and its partner Eisai since fiscal year 2018.
The association applauded the FDA approval but, a few days later, expressed outrage over the $56,000-a-year price tag.
“This price is simply unacceptable,” the Alzheimer’s Association said in the statement. “For many, this price will pose an insurmountable barrier to access, it complicates and jeopardizes sustainable access to this treatment, and may further deepen issues of health equity,” the association said, adding, “We call on Biogen to change this price.”
UsAgainstAlzheimer’s also expressed concerns about access, even before it knew aducanumab’s price.
“Shockingly, Medicare does not reimburse patients for the expensive PET scans important to determine whether someone is appropriate for this drug,” noted George Vradenburg, chairman and cofounder of the group, in a June 7 statement. “We intend to work with Biogen and Medicare to make access to this drug affordable for every American who needs it,” Mr. Vradenburg said.
Dr. Carome said the advocates’ complaints were hard to fathom.
“This should not have come as a surprise to anyone,” Dr. Carome said, adding that “it’s essentially the ballpark figure the company threw out weeks ago.”
“Fifty-six-thousand-dollars is particularly egregiously overpriced for a drug that doesn’t work,” Dr. Carome said. “If the [Alzheimer’s Association] truly finds this objectionable, hopefully they’ll stop accepting money from Biogen and its partner Eisai,” he added.
“The Alzheimer’s Association is recognizing that the genie is out of the bottle and that they are going to have trouble reining in the inevitable run-away costs,” said Mike Greicius, MD, MPH, associate professor of neurology at Stanford University’s Wu Tsai Neurosciences Institute, Stanford, California.
“In addition to the eye-popping annual cost that Biogen has invented, I hope the Alzheimer’s Association is also concerned about the dangerously loose and broad FDA labeling which does not require screening for amyloid-positivity and does not restrict use to the milder forms of disease studied in the Phase 3 trials,” Dr. Greicius said.
Another advocacy group, Patients For Affordable Drugs, commended the Alzheimer’s Association. Its statement “was nothing short of courageous, especially in light of the Alzheimer’s Association’s reliance on funding from drug corporations, including Biogen,” said David Mitchell, a cancer patient and founder of Patients For Affordable Drugs, in a statement.
Mr. Mitchell said his members “stand with the Alzheimer’s Association in its denunciation of the price set by Biogen” and called for a new law that would allow Medicare to negotiate drug prices.
A version of this article first appeared on Medscape.com.
In a letter to the U.S. Department of Health and Human Services Secretary Xavier Becerra, Michael A. Carome, MD, director of Public Citizen’s Health Research Group, said: “The FDA’s decision to approve aducanumab for anyone with Alzheimer’s disease, regardless of severity, showed a stunning disregard for science, eviscerated the agency’s standards for approving new drugs, and ranks as one of the most irresponsible and egregious decisions in the history of the agency.”
Public Citizen urged Mr. Becerra to seek the resignations or the removal of the three FDA officials it said were most responsible for the approval – Acting FDA Commissioner Janet Woodcock, MD; Center for Drug Evaluation and Research (CDER) Director Patrizia Cavazzoni, MD; and CDER’s Office of Neuroscience Director Billy Dunn, MD.
“This decision is a disastrous blow to the agency’s credibility, public health, and the financial sustainability of the Medicare program,” writes Dr. Carome, noting that Biogen said it would charge $56,000 annually for the infusion.
Aaron Kesselheim, MD, one of three FDA Peripheral and Central Nervous System Drugs advisory committee members who resigned in the wake of the approval, agreed with Public Citizen that the agency’s credibility is suffering.
“The aducanumab decision is the worst example yet of the FDA’s movement away from its high standards,” Dr. Kesselheim, a professor of medicine at Harvard Medical School, Boston, and Harvard colleague Jerry Avorn, MD, wrote in the New York Times on June 15.
“As physicians, we know well that Alzheimer’s disease is a terrible condition,” they wrote. However, they added, “approving a drug that has such poor evidence that it works and causes such worrisome side effects is not the solution.”
In his resignation letter, Dr. Kesselheim said he had also been dismayed by the agency’s 2016 approval of eteplirsen (Exondys 51, Sarepta Therapeutics) for Duchenne muscular dystrophy. In both the eteplirsen and aducanumab approvals, the agency went against its advisers’ recommendations, Dr. Kesselheim said.
Advocates who backed approval decry cost
Aducanumab had a rocky road to approval but had unwavering backing from the Alzheimer’s Association and at least one other organization, UsAgainstAlzheimer’s.
The Alzheimer’s Association was particularly outspoken in its support and, in March, was accused of potential conflict of interest by Public Citizen and several neurologists because the association accepted at least $1.4 million from Biogen and its partner Eisai since fiscal year 2018.
The association applauded the FDA approval but, a few days later, expressed outrage over the $56,000-a-year price tag.
“This price is simply unacceptable,” the Alzheimer’s Association said in the statement. “For many, this price will pose an insurmountable barrier to access, it complicates and jeopardizes sustainable access to this treatment, and may further deepen issues of health equity,” the association said, adding, “We call on Biogen to change this price.”
UsAgainstAlzheimer’s also expressed concerns about access, even before it knew aducanumab’s price.
“Shockingly, Medicare does not reimburse patients for the expensive PET scans important to determine whether someone is appropriate for this drug,” noted George Vradenburg, chairman and cofounder of the group, in a June 7 statement. “We intend to work with Biogen and Medicare to make access to this drug affordable for every American who needs it,” Mr. Vradenburg said.
Dr. Carome said the advocates’ complaints were hard to fathom.
“This should not have come as a surprise to anyone,” Dr. Carome said, adding that “it’s essentially the ballpark figure the company threw out weeks ago.”
“Fifty-six-thousand-dollars is particularly egregiously overpriced for a drug that doesn’t work,” Dr. Carome said. “If the [Alzheimer’s Association] truly finds this objectionable, hopefully they’ll stop accepting money from Biogen and its partner Eisai,” he added.
“The Alzheimer’s Association is recognizing that the genie is out of the bottle and that they are going to have trouble reining in the inevitable run-away costs,” said Mike Greicius, MD, MPH, associate professor of neurology at Stanford University’s Wu Tsai Neurosciences Institute, Stanford, California.
“In addition to the eye-popping annual cost that Biogen has invented, I hope the Alzheimer’s Association is also concerned about the dangerously loose and broad FDA labeling which does not require screening for amyloid-positivity and does not restrict use to the milder forms of disease studied in the Phase 3 trials,” Dr. Greicius said.
Another advocacy group, Patients For Affordable Drugs, commended the Alzheimer’s Association. Its statement “was nothing short of courageous, especially in light of the Alzheimer’s Association’s reliance on funding from drug corporations, including Biogen,” said David Mitchell, a cancer patient and founder of Patients For Affordable Drugs, in a statement.
Mr. Mitchell said his members “stand with the Alzheimer’s Association in its denunciation of the price set by Biogen” and called for a new law that would allow Medicare to negotiate drug prices.
A version of this article first appeared on Medscape.com.
The aducanumab revolution
The approval was hailed by advocacy groups and some practitioners as a victory for patients and families, as the drug – the first anti-Alzheimer’s agent to reach the market in 18 years – is a potentially disease-modifying therapy, which acts to clear amyloid plaques from the brain.
But several prominent Alzheimer’s researchers lambasted the agency’s decision, citing unclear evidence of benefit, trials that did not meet their primary endpoints, and reliance on a post hoc analysis of a high-dose subgroup of patients in a halted trial to argue that aducanumab (Aduhelm, Biogen, and Eisai), slowed cognitive and functional decline by 22% on one measure. In November 2020, 10 of 11 members of an independent FDA advisory committee voted against aducanumab’s approval, citing holes in the data and concerns about the quality of the evidence. After the agency went on to approve anyway, three members of that committee resigned in protest.
The FDA decision on aducanumab was made using the agency’s accelerated approval pathway, which allows for the use of a surrogate endpoint – in this case imaging that showed amyloid clearance from the brain – to predict clinical benefit. But amyloid clearance, which a number of experimental antiamyloid antibodies have been shown capable of, has not been definitively linked to clinical benefit. Aducanumab, which is delivered by monthly intravenous infusion, will be marketed pending results from a phase 4 clinical trial, which the manufacturer has nearly a decade to complete. The drug’s price was announced at $56,000 per year, underscoring concern over its modest-at-best benefits.
Clinicians prescribing aducanumab must obtain magnetic resonance imaging at baseline and repeatedly during the course of treatment to detect brain edema and microhemorrhages, which occurred in a third of high-dose patients in clinical trials. Beyond this, there are few restrictions. The FDA label allows for its use in any patient deemed to have Alzheimer’s disease, without stipulations as to disease stage or evidence of brain amyloid. Payers, of course, are likely to restrict use to certain patient groups, and to require evidence of amyloid positivity. The FDA offered no guidance on when treatment should be ceased, leaving payers to make that call as well. Whatever aducanumab’s value and role turns out to be, the first-in-class treatment for Alzheimer’s disease is likely to have a major impact on how patients are assessed and treated in the coming years, and embolden manufactures of similar agents to seek FDA approval.
This news organization reached out to researchers, advocates, and specialists in the community to learn how they see this change playing out.
Fielding broad interest
Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, which was a strong proponent of aducanumab’s approval, acknowledged in an interview that the months to come are likely to be confusing for practitioners and families alike as the drug makes its way into community practices.
“We understand that off the bat millions of Americans will not have access to this tomorrow, but over time that will build. And the physician community, the specialists most likely to be prescribing this, over the next few years will even expand further,” Dr. Carrillo said.
For now, those specialists are mostly just struggling to respond responsibly to a deluge of inquiries from patients and their families.
“I’ve gotten like 20 calls in the just the past 2 days,” said neurologist Philip R. Delio, MD, who practices in Santa Barbara, Calif. “This is a longstanding issue that physicians have with patients’ access to information. Patients are getting information about a drug which isn’t available yet. They don’t know that it’s not ready to be sold. They don’t necessarily realize that a biopharma company won’t go into production until the FDA approves the drug.”
Many patients, Dr. Delio said, are aware of the controversy surrounding aducanumab and eager to hear their neurologist’s opinion. “I have tried to let them know that I want to see the trial data and to better understand the FDA’s rationale in approving it. I always caution patients that the devil will be in the details.”
While aducanumab’s label gives physicians remarkably wide latitude in whom to treat, clinicians say that until payers weigh in, the label is all but meaningless. Neurologist Douglas Scharre, MD, of the Ohio State University Wexner Medical Center, and a site investigator on a trial of aducanumab, said that he and his colleagues at the university’s memory center have tried to anticipate who might be deemed eligible by triaging calls.
Dr. Scharre and colleagues have been working under the assumption that payers will support aducanumab only for patients like those who seemed to benefit in the trials – people with mild cognitive impairment (MCI) or in the earliest stages of dementia with evidence of brain amyloid.
“I don’t want to fill up our new patient slots with people who are not even appropriate for this drug,” Dr. Scharre said. “We have a call center, and we have a few triage questions. After that a nurse practitioner collects some more data, and there’s a review process. Only then do we decide whether that person could be a candidate. If we deem that they are, we will want them in and to order an amyloid PET” – a type of brain scan that is seldom used outside research settings and not reimbursed by Medicare.
Dr. Scharre predicts that regardless of payer limitations, “there will be people hounding for the drug who are not appropriate for the drug. There will be very wealthy people who will want to pay for tests and get it no matter what.” Another concern, he said, was that having poorly selected patients on the drug could make definitive trial results even more elusive.
“The label the way it’s written is not going to help the drug in phase 4 trials,” he said. “It’s good to have real-world patient data, but if you have all these people in your cohort who are too early or too late, you won’t have good results.”
The challenge of delivery
Intravenous infusions are new to Alzheimer’s disease and pose all sorts of logistical hurdles. The Alzheimer’s Association’s Dr. Carrillo described the situation as “manageable,” noting that infusions are standard of care for many diseases, and that neurologists now have more than 15 years’ experience with them for multiple sclerosis.
Still, most clinicians treating Alzheimer’s disease in the community – neurologists, geriatricians, psychiatrists, and primary care physicians – do not have infusion centers in their practices. Virtually none have experience with or access to PET-amyloid, or with screening for amyloid-related imaging abnormalities–edema (ARIA-e) on MRI, as required by the FDA.
“I contacted the hospital infusion center we use and said I could end up sending five or six patients a week, can you handle this? They only have so many chairs,” Dr. Delio said. “I am one neurologist in a local community, and I might have 50 candidates for this drug. That’s a lot for them.” Patients with cognitive impairment are also difficult to infuse and may need to be treated at home, he noted.
“MRIs are easy enough to do,” Dr. Delio said. “But do we know what ARIA-e looks like on imaging? You’d have to talk to the radiologists – this is another element of uncertainty. Do we even know what we’re looking for with these scans? Will we recognize this?”
Neurologist Jeffrey L. Cummings, MD, ScD, of the University of Nevada, Las Vegas, a vocal proponent of aducanumab and lead author of a May 2021 paper defending the evidence for it, acknowledged that the field was unprepared for a wide-scale adoption of infusions in dementia treatment, pointing to a Rand Corporation study from 2017 that warned that screening, diagnosis, and availability of infusion chairs would have to be drastically scaled up to meet demand.
“There are few clinicians who know how to identify MCI, too few imaging centers, too few radiologists who know how to identify ARIA-e on MRI, so all of these things will be required to be put into place. The label doesn’t specify any of this, but good clinical practice will require that, and getting this up and running will take 18 to 24 months,” Dr. Cummings said.
Neurologist David S. Knopman, MD, of the Mayo Clinic in Rochester, Minn., a leading critic of the evidence for aducanumab who recently resigned his position on the independent committee that advises the FDA on neurology drugs, said that for large research institutions like his that have served as trial sites, the transition to offering PET-amyloid, MRI, and infusions in clinical practice will be easier.
“We have all this because this is what we do every day. And we have a very extensive understanding of MCI and mild dementia staging,” Dr. Knopman said. “But the amount of infrastructure that is implied by this, and all the extra steps it would take, would be a real challenge for people in general neurology practice.”
In addition to routine use of PET-amyloid and MRI screening for ARIA-e, Dr. Knopman said, clinicians will have to provide genetic screening and counseling before administering aducanumab, as clinical trials showed that treated patients have a higher risk of developing ARIA-e if they have APOE4, a risk variant for Alzheimer’s disease. “And that has real implications for the families and the children of patients,” he said.
Uncertainty over costs
Aducanumab’s true costs, to patients and to taxpayers, remain unknown. The $56,000 per year currently cited by its manufacturer “doesn’t count the PET scans and MRIs,” Dr. Knopman noted. “We’re probably pushing $100,00 a year for the first year of treatment.”
Most of that expense will likely be borne by Medicare, he said, and if not, “that will exacerbate existing health care disparities. People who can pay out of pocket are a pretty limited group.”
Dr. Scharre agreed that the costs of treatment were concerning, and that “at least you should be able to narrow it down and hopefully just use health care dollars for people who might stand to benefit,” he said – namely patients in an earlier stage of disease.
The Alzheimer’s Association’s Dr. Carrillo declined to address the high price of aducanumab or its implications, saying only that the association is “very invested in all aspects of access including covering costs associated with the drug and the rest of treatment.”
Access also means “infrastructure, access to physicians to diagnose, access to diagnostics,” Dr. Carrillo said.
Dr. Cummings said aducanumab’s price would likely come down through negotiations with the Centers for Medicare & Medicaid Services, copayments, and bulk purchases.
The FDA has offered no guidance on how long treatment with aducanumab should last, or what should prompt withdrawal of treatment, meaning that patients could, in theory, stay on it to the end of their lives – raising costs further.
Critics have also noted that a built-in financial incentive under Medicare Part B, which covers infusion drugs, could result in overprescription of aducanumab. Under Medicare Part B, prescribing physicians are reimbursed 6% of a drug’s average sales price.
Geriatricians wary
On social media and in the lay press, geriatricians have been among the most outspoken opponents of the FDA decision and the Alzheimer’s Association’s advocacy of aducanumab.
Eric Widera, MD, a geriatrician at the University of California, San Francisco, said that the specialty might be less likely than others to embrace aducanumab. “I think part of the reasons geriatricians don’t make a lot of money is they have strong commitment to their values,” Dr. Widera said.
The American Geriatrics Society opposed the drug’s approval, citing concerns about evidence, side effects, and cost. “Additional considerations are the unintended consequences of overstressing Medicare’s limited financial reserves, and of challenging health care systems … to divert precious resources to an expensive treatment of uncertain value,” the society’s president, Peter Hollmann, MD, and chief executive officer, Nancy E. Lundebjerg, wrote in a June 2 letter to the FDA.
Dr. Widera said the approval was likely to undermine confidence in the FDA and in the Alzheimer’s Association, which receives significant funding from drug manufacturers, including Biogen and Eisai. “There’s a lot of reasons that the Geriatrics Society could have done what the Alzheimer’s Association did, and yet they came out against it, which I applaud.”
Dr. Widera pointed to a study showing that dementia patients were less likely to be on an antidementia drug if they were treated by a geriatrician, compared with a psychiatrist or a neurologist. But whether the specialty will prove as cautious with aducanumab remains to be seen. Some geriatricians will be tempted to open lucrative infusion centers, he predicted.
What is especially worrisome, Dr. Widera said, is that aducanumab’s label offers no guidance as to when to withdraw treatment. “We’ll probably see something similar to what happened with the cholinesterase inhibitors” – the class of marginally effective antidementia drugs that includes donepezil (Aricept, Pfizer) and rivastigmine (Exelon, Novartis). “No one thinks about deprescribing them. People are prescribed them even in their last months of life. There is no reason to think these infusions won’t be continued for a very long time, well beyond how long people were dosed in the trials.”
“Taking care of someone with dementia is hard enough,” Dr. Widera added. “We can’t even get normal support in the home for someone with dementia. But we are more than happy to throw money to Biogen for a drug they have not yet showed benefit for. Hopefully in 5 years we’ll have a drug that actually works,” Dr. Widera said. “After 5 years of giving this to people at $50,000 a year.”
A fractured research community
Ever since October 2019, when Biogen and Eisai announced that despite two trials halted for futility, they would go ahead and seek FDA approval for aducanumab, the Alzheimer’s research community has been bitterly divided over the drug and the FDA’s accelerated approval process.
Top researchers published critical editorials in journals, with some eventually taking their case to major newspapers as well. The Alzheimer’s Association’s position on the drug has clashed with that of many researchers whose work it supports.
“The Alzheimer’s community has been wonderfully collegial – we all have a common purpose,” Dr. Cummings said. “Now we have people taking extreme positions and I’m hoping this will not result in a permanent fracturing of the community.”
Chief among the critics’ concerns is that the FDA decision ratified the use of antiamyloid therapies based on biomarker evidence, opening the door for makers of similar drugs – those still under development or even those whose development has been halted – to seek approval on weak evidence of clinical benefit.
Whether the approval will chill research into drugs targeting pathways other than amyloid is uncertain.
Dr. Cummings said he felt that while the aducanumab decision would spur other manufacturers of antiamyloid drugs to seek accelerated approval, other classes of Alzheimer’s therapies in development also stand to get a boost. Many Alzheimer’s experts believe that a combination of drugs targeting different elements of the disease pathway – not just amyloid – will be needed in the long run.
Dr. Scharre said that the buzz over aducanumab’s approval will have at least one concrete benefit: people getting into doctors’ offices sooner.
“The people who come into our memory centers represent only a fraction of people walking around with MCI – there are people out there who may have heard that it’s normal aging; they have decreased insight; there’s denial, there’s embarrassment – there’s hundreds of reasons people avoid getting seen,” he said.
“Perhaps they come in and learn that they don’t have any degenerative process but their thyroid is out of whack, or there’s something else causing cognitive impairment. And if they do have a degenerative process, they’ll have time to start [aducanumab], and hopefully get to see a reduction in the decline.”
Dr. Knopman was a site investigator for the Biogen aducanumab trials and has consulted for Samus Therapeutics, Third Rock, Roche, and Alzeca Biosciences. A former member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, he was recused from the Nov. 6, 2020, meeting that voted against aducanumab. Dr. Cummings has consulted for Biogen, Eisai, and other manufacturers. Dr. Scharre reports financial relationships with Biogen, Brain Test, Acadia, and Vascular Scientific. Dr. Widera has no disclosures. Dr. Delio is a speaker for Gore Medical, Allergan, and Biohaven Pharmaceuticals.
The approval was hailed by advocacy groups and some practitioners as a victory for patients and families, as the drug – the first anti-Alzheimer’s agent to reach the market in 18 years – is a potentially disease-modifying therapy, which acts to clear amyloid plaques from the brain.
But several prominent Alzheimer’s researchers lambasted the agency’s decision, citing unclear evidence of benefit, trials that did not meet their primary endpoints, and reliance on a post hoc analysis of a high-dose subgroup of patients in a halted trial to argue that aducanumab (Aduhelm, Biogen, and Eisai), slowed cognitive and functional decline by 22% on one measure. In November 2020, 10 of 11 members of an independent FDA advisory committee voted against aducanumab’s approval, citing holes in the data and concerns about the quality of the evidence. After the agency went on to approve anyway, three members of that committee resigned in protest.
The FDA decision on aducanumab was made using the agency’s accelerated approval pathway, which allows for the use of a surrogate endpoint – in this case imaging that showed amyloid clearance from the brain – to predict clinical benefit. But amyloid clearance, which a number of experimental antiamyloid antibodies have been shown capable of, has not been definitively linked to clinical benefit. Aducanumab, which is delivered by monthly intravenous infusion, will be marketed pending results from a phase 4 clinical trial, which the manufacturer has nearly a decade to complete. The drug’s price was announced at $56,000 per year, underscoring concern over its modest-at-best benefits.
Clinicians prescribing aducanumab must obtain magnetic resonance imaging at baseline and repeatedly during the course of treatment to detect brain edema and microhemorrhages, which occurred in a third of high-dose patients in clinical trials. Beyond this, there are few restrictions. The FDA label allows for its use in any patient deemed to have Alzheimer’s disease, without stipulations as to disease stage or evidence of brain amyloid. Payers, of course, are likely to restrict use to certain patient groups, and to require evidence of amyloid positivity. The FDA offered no guidance on when treatment should be ceased, leaving payers to make that call as well. Whatever aducanumab’s value and role turns out to be, the first-in-class treatment for Alzheimer’s disease is likely to have a major impact on how patients are assessed and treated in the coming years, and embolden manufactures of similar agents to seek FDA approval.
This news organization reached out to researchers, advocates, and specialists in the community to learn how they see this change playing out.
Fielding broad interest
Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, which was a strong proponent of aducanumab’s approval, acknowledged in an interview that the months to come are likely to be confusing for practitioners and families alike as the drug makes its way into community practices.
“We understand that off the bat millions of Americans will not have access to this tomorrow, but over time that will build. And the physician community, the specialists most likely to be prescribing this, over the next few years will even expand further,” Dr. Carrillo said.
For now, those specialists are mostly just struggling to respond responsibly to a deluge of inquiries from patients and their families.
“I’ve gotten like 20 calls in the just the past 2 days,” said neurologist Philip R. Delio, MD, who practices in Santa Barbara, Calif. “This is a longstanding issue that physicians have with patients’ access to information. Patients are getting information about a drug which isn’t available yet. They don’t know that it’s not ready to be sold. They don’t necessarily realize that a biopharma company won’t go into production until the FDA approves the drug.”
Many patients, Dr. Delio said, are aware of the controversy surrounding aducanumab and eager to hear their neurologist’s opinion. “I have tried to let them know that I want to see the trial data and to better understand the FDA’s rationale in approving it. I always caution patients that the devil will be in the details.”
While aducanumab’s label gives physicians remarkably wide latitude in whom to treat, clinicians say that until payers weigh in, the label is all but meaningless. Neurologist Douglas Scharre, MD, of the Ohio State University Wexner Medical Center, and a site investigator on a trial of aducanumab, said that he and his colleagues at the university’s memory center have tried to anticipate who might be deemed eligible by triaging calls.
Dr. Scharre and colleagues have been working under the assumption that payers will support aducanumab only for patients like those who seemed to benefit in the trials – people with mild cognitive impairment (MCI) or in the earliest stages of dementia with evidence of brain amyloid.
“I don’t want to fill up our new patient slots with people who are not even appropriate for this drug,” Dr. Scharre said. “We have a call center, and we have a few triage questions. After that a nurse practitioner collects some more data, and there’s a review process. Only then do we decide whether that person could be a candidate. If we deem that they are, we will want them in and to order an amyloid PET” – a type of brain scan that is seldom used outside research settings and not reimbursed by Medicare.
Dr. Scharre predicts that regardless of payer limitations, “there will be people hounding for the drug who are not appropriate for the drug. There will be very wealthy people who will want to pay for tests and get it no matter what.” Another concern, he said, was that having poorly selected patients on the drug could make definitive trial results even more elusive.
“The label the way it’s written is not going to help the drug in phase 4 trials,” he said. “It’s good to have real-world patient data, but if you have all these people in your cohort who are too early or too late, you won’t have good results.”
The challenge of delivery
Intravenous infusions are new to Alzheimer’s disease and pose all sorts of logistical hurdles. The Alzheimer’s Association’s Dr. Carrillo described the situation as “manageable,” noting that infusions are standard of care for many diseases, and that neurologists now have more than 15 years’ experience with them for multiple sclerosis.
Still, most clinicians treating Alzheimer’s disease in the community – neurologists, geriatricians, psychiatrists, and primary care physicians – do not have infusion centers in their practices. Virtually none have experience with or access to PET-amyloid, or with screening for amyloid-related imaging abnormalities–edema (ARIA-e) on MRI, as required by the FDA.
“I contacted the hospital infusion center we use and said I could end up sending five or six patients a week, can you handle this? They only have so many chairs,” Dr. Delio said. “I am one neurologist in a local community, and I might have 50 candidates for this drug. That’s a lot for them.” Patients with cognitive impairment are also difficult to infuse and may need to be treated at home, he noted.
“MRIs are easy enough to do,” Dr. Delio said. “But do we know what ARIA-e looks like on imaging? You’d have to talk to the radiologists – this is another element of uncertainty. Do we even know what we’re looking for with these scans? Will we recognize this?”
Neurologist Jeffrey L. Cummings, MD, ScD, of the University of Nevada, Las Vegas, a vocal proponent of aducanumab and lead author of a May 2021 paper defending the evidence for it, acknowledged that the field was unprepared for a wide-scale adoption of infusions in dementia treatment, pointing to a Rand Corporation study from 2017 that warned that screening, diagnosis, and availability of infusion chairs would have to be drastically scaled up to meet demand.
“There are few clinicians who know how to identify MCI, too few imaging centers, too few radiologists who know how to identify ARIA-e on MRI, so all of these things will be required to be put into place. The label doesn’t specify any of this, but good clinical practice will require that, and getting this up and running will take 18 to 24 months,” Dr. Cummings said.
Neurologist David S. Knopman, MD, of the Mayo Clinic in Rochester, Minn., a leading critic of the evidence for aducanumab who recently resigned his position on the independent committee that advises the FDA on neurology drugs, said that for large research institutions like his that have served as trial sites, the transition to offering PET-amyloid, MRI, and infusions in clinical practice will be easier.
“We have all this because this is what we do every day. And we have a very extensive understanding of MCI and mild dementia staging,” Dr. Knopman said. “But the amount of infrastructure that is implied by this, and all the extra steps it would take, would be a real challenge for people in general neurology practice.”
In addition to routine use of PET-amyloid and MRI screening for ARIA-e, Dr. Knopman said, clinicians will have to provide genetic screening and counseling before administering aducanumab, as clinical trials showed that treated patients have a higher risk of developing ARIA-e if they have APOE4, a risk variant for Alzheimer’s disease. “And that has real implications for the families and the children of patients,” he said.
Uncertainty over costs
Aducanumab’s true costs, to patients and to taxpayers, remain unknown. The $56,000 per year currently cited by its manufacturer “doesn’t count the PET scans and MRIs,” Dr. Knopman noted. “We’re probably pushing $100,00 a year for the first year of treatment.”
Most of that expense will likely be borne by Medicare, he said, and if not, “that will exacerbate existing health care disparities. People who can pay out of pocket are a pretty limited group.”
Dr. Scharre agreed that the costs of treatment were concerning, and that “at least you should be able to narrow it down and hopefully just use health care dollars for people who might stand to benefit,” he said – namely patients in an earlier stage of disease.
The Alzheimer’s Association’s Dr. Carrillo declined to address the high price of aducanumab or its implications, saying only that the association is “very invested in all aspects of access including covering costs associated with the drug and the rest of treatment.”
Access also means “infrastructure, access to physicians to diagnose, access to diagnostics,” Dr. Carrillo said.
Dr. Cummings said aducanumab’s price would likely come down through negotiations with the Centers for Medicare & Medicaid Services, copayments, and bulk purchases.
The FDA has offered no guidance on how long treatment with aducanumab should last, or what should prompt withdrawal of treatment, meaning that patients could, in theory, stay on it to the end of their lives – raising costs further.
Critics have also noted that a built-in financial incentive under Medicare Part B, which covers infusion drugs, could result in overprescription of aducanumab. Under Medicare Part B, prescribing physicians are reimbursed 6% of a drug’s average sales price.
Geriatricians wary
On social media and in the lay press, geriatricians have been among the most outspoken opponents of the FDA decision and the Alzheimer’s Association’s advocacy of aducanumab.
Eric Widera, MD, a geriatrician at the University of California, San Francisco, said that the specialty might be less likely than others to embrace aducanumab. “I think part of the reasons geriatricians don’t make a lot of money is they have strong commitment to their values,” Dr. Widera said.
The American Geriatrics Society opposed the drug’s approval, citing concerns about evidence, side effects, and cost. “Additional considerations are the unintended consequences of overstressing Medicare’s limited financial reserves, and of challenging health care systems … to divert precious resources to an expensive treatment of uncertain value,” the society’s president, Peter Hollmann, MD, and chief executive officer, Nancy E. Lundebjerg, wrote in a June 2 letter to the FDA.
Dr. Widera said the approval was likely to undermine confidence in the FDA and in the Alzheimer’s Association, which receives significant funding from drug manufacturers, including Biogen and Eisai. “There’s a lot of reasons that the Geriatrics Society could have done what the Alzheimer’s Association did, and yet they came out against it, which I applaud.”
Dr. Widera pointed to a study showing that dementia patients were less likely to be on an antidementia drug if they were treated by a geriatrician, compared with a psychiatrist or a neurologist. But whether the specialty will prove as cautious with aducanumab remains to be seen. Some geriatricians will be tempted to open lucrative infusion centers, he predicted.
What is especially worrisome, Dr. Widera said, is that aducanumab’s label offers no guidance as to when to withdraw treatment. “We’ll probably see something similar to what happened with the cholinesterase inhibitors” – the class of marginally effective antidementia drugs that includes donepezil (Aricept, Pfizer) and rivastigmine (Exelon, Novartis). “No one thinks about deprescribing them. People are prescribed them even in their last months of life. There is no reason to think these infusions won’t be continued for a very long time, well beyond how long people were dosed in the trials.”
“Taking care of someone with dementia is hard enough,” Dr. Widera added. “We can’t even get normal support in the home for someone with dementia. But we are more than happy to throw money to Biogen for a drug they have not yet showed benefit for. Hopefully in 5 years we’ll have a drug that actually works,” Dr. Widera said. “After 5 years of giving this to people at $50,000 a year.”
A fractured research community
Ever since October 2019, when Biogen and Eisai announced that despite two trials halted for futility, they would go ahead and seek FDA approval for aducanumab, the Alzheimer’s research community has been bitterly divided over the drug and the FDA’s accelerated approval process.
Top researchers published critical editorials in journals, with some eventually taking their case to major newspapers as well. The Alzheimer’s Association’s position on the drug has clashed with that of many researchers whose work it supports.
“The Alzheimer’s community has been wonderfully collegial – we all have a common purpose,” Dr. Cummings said. “Now we have people taking extreme positions and I’m hoping this will not result in a permanent fracturing of the community.”
Chief among the critics’ concerns is that the FDA decision ratified the use of antiamyloid therapies based on biomarker evidence, opening the door for makers of similar drugs – those still under development or even those whose development has been halted – to seek approval on weak evidence of clinical benefit.
Whether the approval will chill research into drugs targeting pathways other than amyloid is uncertain.
Dr. Cummings said he felt that while the aducanumab decision would spur other manufacturers of antiamyloid drugs to seek accelerated approval, other classes of Alzheimer’s therapies in development also stand to get a boost. Many Alzheimer’s experts believe that a combination of drugs targeting different elements of the disease pathway – not just amyloid – will be needed in the long run.
Dr. Scharre said that the buzz over aducanumab’s approval will have at least one concrete benefit: people getting into doctors’ offices sooner.
“The people who come into our memory centers represent only a fraction of people walking around with MCI – there are people out there who may have heard that it’s normal aging; they have decreased insight; there’s denial, there’s embarrassment – there’s hundreds of reasons people avoid getting seen,” he said.
“Perhaps they come in and learn that they don’t have any degenerative process but their thyroid is out of whack, or there’s something else causing cognitive impairment. And if they do have a degenerative process, they’ll have time to start [aducanumab], and hopefully get to see a reduction in the decline.”
Dr. Knopman was a site investigator for the Biogen aducanumab trials and has consulted for Samus Therapeutics, Third Rock, Roche, and Alzeca Biosciences. A former member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, he was recused from the Nov. 6, 2020, meeting that voted against aducanumab. Dr. Cummings has consulted for Biogen, Eisai, and other manufacturers. Dr. Scharre reports financial relationships with Biogen, Brain Test, Acadia, and Vascular Scientific. Dr. Widera has no disclosures. Dr. Delio is a speaker for Gore Medical, Allergan, and Biohaven Pharmaceuticals.
The approval was hailed by advocacy groups and some practitioners as a victory for patients and families, as the drug – the first anti-Alzheimer’s agent to reach the market in 18 years – is a potentially disease-modifying therapy, which acts to clear amyloid plaques from the brain.
But several prominent Alzheimer’s researchers lambasted the agency’s decision, citing unclear evidence of benefit, trials that did not meet their primary endpoints, and reliance on a post hoc analysis of a high-dose subgroup of patients in a halted trial to argue that aducanumab (Aduhelm, Biogen, and Eisai), slowed cognitive and functional decline by 22% on one measure. In November 2020, 10 of 11 members of an independent FDA advisory committee voted against aducanumab’s approval, citing holes in the data and concerns about the quality of the evidence. After the agency went on to approve anyway, three members of that committee resigned in protest.
The FDA decision on aducanumab was made using the agency’s accelerated approval pathway, which allows for the use of a surrogate endpoint – in this case imaging that showed amyloid clearance from the brain – to predict clinical benefit. But amyloid clearance, which a number of experimental antiamyloid antibodies have been shown capable of, has not been definitively linked to clinical benefit. Aducanumab, which is delivered by monthly intravenous infusion, will be marketed pending results from a phase 4 clinical trial, which the manufacturer has nearly a decade to complete. The drug’s price was announced at $56,000 per year, underscoring concern over its modest-at-best benefits.
Clinicians prescribing aducanumab must obtain magnetic resonance imaging at baseline and repeatedly during the course of treatment to detect brain edema and microhemorrhages, which occurred in a third of high-dose patients in clinical trials. Beyond this, there are few restrictions. The FDA label allows for its use in any patient deemed to have Alzheimer’s disease, without stipulations as to disease stage or evidence of brain amyloid. Payers, of course, are likely to restrict use to certain patient groups, and to require evidence of amyloid positivity. The FDA offered no guidance on when treatment should be ceased, leaving payers to make that call as well. Whatever aducanumab’s value and role turns out to be, the first-in-class treatment for Alzheimer’s disease is likely to have a major impact on how patients are assessed and treated in the coming years, and embolden manufactures of similar agents to seek FDA approval.
This news organization reached out to researchers, advocates, and specialists in the community to learn how they see this change playing out.
Fielding broad interest
Maria C. Carrillo, PhD, chief science officer of the Alzheimer’s Association, which was a strong proponent of aducanumab’s approval, acknowledged in an interview that the months to come are likely to be confusing for practitioners and families alike as the drug makes its way into community practices.
“We understand that off the bat millions of Americans will not have access to this tomorrow, but over time that will build. And the physician community, the specialists most likely to be prescribing this, over the next few years will even expand further,” Dr. Carrillo said.
For now, those specialists are mostly just struggling to respond responsibly to a deluge of inquiries from patients and their families.
“I’ve gotten like 20 calls in the just the past 2 days,” said neurologist Philip R. Delio, MD, who practices in Santa Barbara, Calif. “This is a longstanding issue that physicians have with patients’ access to information. Patients are getting information about a drug which isn’t available yet. They don’t know that it’s not ready to be sold. They don’t necessarily realize that a biopharma company won’t go into production until the FDA approves the drug.”
Many patients, Dr. Delio said, are aware of the controversy surrounding aducanumab and eager to hear their neurologist’s opinion. “I have tried to let them know that I want to see the trial data and to better understand the FDA’s rationale in approving it. I always caution patients that the devil will be in the details.”
While aducanumab’s label gives physicians remarkably wide latitude in whom to treat, clinicians say that until payers weigh in, the label is all but meaningless. Neurologist Douglas Scharre, MD, of the Ohio State University Wexner Medical Center, and a site investigator on a trial of aducanumab, said that he and his colleagues at the university’s memory center have tried to anticipate who might be deemed eligible by triaging calls.
Dr. Scharre and colleagues have been working under the assumption that payers will support aducanumab only for patients like those who seemed to benefit in the trials – people with mild cognitive impairment (MCI) or in the earliest stages of dementia with evidence of brain amyloid.
“I don’t want to fill up our new patient slots with people who are not even appropriate for this drug,” Dr. Scharre said. “We have a call center, and we have a few triage questions. After that a nurse practitioner collects some more data, and there’s a review process. Only then do we decide whether that person could be a candidate. If we deem that they are, we will want them in and to order an amyloid PET” – a type of brain scan that is seldom used outside research settings and not reimbursed by Medicare.
Dr. Scharre predicts that regardless of payer limitations, “there will be people hounding for the drug who are not appropriate for the drug. There will be very wealthy people who will want to pay for tests and get it no matter what.” Another concern, he said, was that having poorly selected patients on the drug could make definitive trial results even more elusive.
“The label the way it’s written is not going to help the drug in phase 4 trials,” he said. “It’s good to have real-world patient data, but if you have all these people in your cohort who are too early or too late, you won’t have good results.”
The challenge of delivery
Intravenous infusions are new to Alzheimer’s disease and pose all sorts of logistical hurdles. The Alzheimer’s Association’s Dr. Carrillo described the situation as “manageable,” noting that infusions are standard of care for many diseases, and that neurologists now have more than 15 years’ experience with them for multiple sclerosis.
Still, most clinicians treating Alzheimer’s disease in the community – neurologists, geriatricians, psychiatrists, and primary care physicians – do not have infusion centers in their practices. Virtually none have experience with or access to PET-amyloid, or with screening for amyloid-related imaging abnormalities–edema (ARIA-e) on MRI, as required by the FDA.
“I contacted the hospital infusion center we use and said I could end up sending five or six patients a week, can you handle this? They only have so many chairs,” Dr. Delio said. “I am one neurologist in a local community, and I might have 50 candidates for this drug. That’s a lot for them.” Patients with cognitive impairment are also difficult to infuse and may need to be treated at home, he noted.
“MRIs are easy enough to do,” Dr. Delio said. “But do we know what ARIA-e looks like on imaging? You’d have to talk to the radiologists – this is another element of uncertainty. Do we even know what we’re looking for with these scans? Will we recognize this?”
Neurologist Jeffrey L. Cummings, MD, ScD, of the University of Nevada, Las Vegas, a vocal proponent of aducanumab and lead author of a May 2021 paper defending the evidence for it, acknowledged that the field was unprepared for a wide-scale adoption of infusions in dementia treatment, pointing to a Rand Corporation study from 2017 that warned that screening, diagnosis, and availability of infusion chairs would have to be drastically scaled up to meet demand.
“There are few clinicians who know how to identify MCI, too few imaging centers, too few radiologists who know how to identify ARIA-e on MRI, so all of these things will be required to be put into place. The label doesn’t specify any of this, but good clinical practice will require that, and getting this up and running will take 18 to 24 months,” Dr. Cummings said.
Neurologist David S. Knopman, MD, of the Mayo Clinic in Rochester, Minn., a leading critic of the evidence for aducanumab who recently resigned his position on the independent committee that advises the FDA on neurology drugs, said that for large research institutions like his that have served as trial sites, the transition to offering PET-amyloid, MRI, and infusions in clinical practice will be easier.
“We have all this because this is what we do every day. And we have a very extensive understanding of MCI and mild dementia staging,” Dr. Knopman said. “But the amount of infrastructure that is implied by this, and all the extra steps it would take, would be a real challenge for people in general neurology practice.”
In addition to routine use of PET-amyloid and MRI screening for ARIA-e, Dr. Knopman said, clinicians will have to provide genetic screening and counseling before administering aducanumab, as clinical trials showed that treated patients have a higher risk of developing ARIA-e if they have APOE4, a risk variant for Alzheimer’s disease. “And that has real implications for the families and the children of patients,” he said.
Uncertainty over costs
Aducanumab’s true costs, to patients and to taxpayers, remain unknown. The $56,000 per year currently cited by its manufacturer “doesn’t count the PET scans and MRIs,” Dr. Knopman noted. “We’re probably pushing $100,00 a year for the first year of treatment.”
Most of that expense will likely be borne by Medicare, he said, and if not, “that will exacerbate existing health care disparities. People who can pay out of pocket are a pretty limited group.”
Dr. Scharre agreed that the costs of treatment were concerning, and that “at least you should be able to narrow it down and hopefully just use health care dollars for people who might stand to benefit,” he said – namely patients in an earlier stage of disease.
The Alzheimer’s Association’s Dr. Carrillo declined to address the high price of aducanumab or its implications, saying only that the association is “very invested in all aspects of access including covering costs associated with the drug and the rest of treatment.”
Access also means “infrastructure, access to physicians to diagnose, access to diagnostics,” Dr. Carrillo said.
Dr. Cummings said aducanumab’s price would likely come down through negotiations with the Centers for Medicare & Medicaid Services, copayments, and bulk purchases.
The FDA has offered no guidance on how long treatment with aducanumab should last, or what should prompt withdrawal of treatment, meaning that patients could, in theory, stay on it to the end of their lives – raising costs further.
Critics have also noted that a built-in financial incentive under Medicare Part B, which covers infusion drugs, could result in overprescription of aducanumab. Under Medicare Part B, prescribing physicians are reimbursed 6% of a drug’s average sales price.
Geriatricians wary
On social media and in the lay press, geriatricians have been among the most outspoken opponents of the FDA decision and the Alzheimer’s Association’s advocacy of aducanumab.
Eric Widera, MD, a geriatrician at the University of California, San Francisco, said that the specialty might be less likely than others to embrace aducanumab. “I think part of the reasons geriatricians don’t make a lot of money is they have strong commitment to their values,” Dr. Widera said.
The American Geriatrics Society opposed the drug’s approval, citing concerns about evidence, side effects, and cost. “Additional considerations are the unintended consequences of overstressing Medicare’s limited financial reserves, and of challenging health care systems … to divert precious resources to an expensive treatment of uncertain value,” the society’s president, Peter Hollmann, MD, and chief executive officer, Nancy E. Lundebjerg, wrote in a June 2 letter to the FDA.
Dr. Widera said the approval was likely to undermine confidence in the FDA and in the Alzheimer’s Association, which receives significant funding from drug manufacturers, including Biogen and Eisai. “There’s a lot of reasons that the Geriatrics Society could have done what the Alzheimer’s Association did, and yet they came out against it, which I applaud.”
Dr. Widera pointed to a study showing that dementia patients were less likely to be on an antidementia drug if they were treated by a geriatrician, compared with a psychiatrist or a neurologist. But whether the specialty will prove as cautious with aducanumab remains to be seen. Some geriatricians will be tempted to open lucrative infusion centers, he predicted.
What is especially worrisome, Dr. Widera said, is that aducanumab’s label offers no guidance as to when to withdraw treatment. “We’ll probably see something similar to what happened with the cholinesterase inhibitors” – the class of marginally effective antidementia drugs that includes donepezil (Aricept, Pfizer) and rivastigmine (Exelon, Novartis). “No one thinks about deprescribing them. People are prescribed them even in their last months of life. There is no reason to think these infusions won’t be continued for a very long time, well beyond how long people were dosed in the trials.”
“Taking care of someone with dementia is hard enough,” Dr. Widera added. “We can’t even get normal support in the home for someone with dementia. But we are more than happy to throw money to Biogen for a drug they have not yet showed benefit for. Hopefully in 5 years we’ll have a drug that actually works,” Dr. Widera said. “After 5 years of giving this to people at $50,000 a year.”
A fractured research community
Ever since October 2019, when Biogen and Eisai announced that despite two trials halted for futility, they would go ahead and seek FDA approval for aducanumab, the Alzheimer’s research community has been bitterly divided over the drug and the FDA’s accelerated approval process.
Top researchers published critical editorials in journals, with some eventually taking their case to major newspapers as well. The Alzheimer’s Association’s position on the drug has clashed with that of many researchers whose work it supports.
“The Alzheimer’s community has been wonderfully collegial – we all have a common purpose,” Dr. Cummings said. “Now we have people taking extreme positions and I’m hoping this will not result in a permanent fracturing of the community.”
Chief among the critics’ concerns is that the FDA decision ratified the use of antiamyloid therapies based on biomarker evidence, opening the door for makers of similar drugs – those still under development or even those whose development has been halted – to seek approval on weak evidence of clinical benefit.
Whether the approval will chill research into drugs targeting pathways other than amyloid is uncertain.
Dr. Cummings said he felt that while the aducanumab decision would spur other manufacturers of antiamyloid drugs to seek accelerated approval, other classes of Alzheimer’s therapies in development also stand to get a boost. Many Alzheimer’s experts believe that a combination of drugs targeting different elements of the disease pathway – not just amyloid – will be needed in the long run.
Dr. Scharre said that the buzz over aducanumab’s approval will have at least one concrete benefit: people getting into doctors’ offices sooner.
“The people who come into our memory centers represent only a fraction of people walking around with MCI – there are people out there who may have heard that it’s normal aging; they have decreased insight; there’s denial, there’s embarrassment – there’s hundreds of reasons people avoid getting seen,” he said.
“Perhaps they come in and learn that they don’t have any degenerative process but their thyroid is out of whack, or there’s something else causing cognitive impairment. And if they do have a degenerative process, they’ll have time to start [aducanumab], and hopefully get to see a reduction in the decline.”
Dr. Knopman was a site investigator for the Biogen aducanumab trials and has consulted for Samus Therapeutics, Third Rock, Roche, and Alzeca Biosciences. A former member of the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee, he was recused from the Nov. 6, 2020, meeting that voted against aducanumab. Dr. Cummings has consulted for Biogen, Eisai, and other manufacturers. Dr. Scharre reports financial relationships with Biogen, Brain Test, Acadia, and Vascular Scientific. Dr. Widera has no disclosures. Dr. Delio is a speaker for Gore Medical, Allergan, and Biohaven Pharmaceuticals.
Choosing the right R-CHOP dosage for elderly patients with DLBCL
Physicians often face the choice of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone + rituximab), according to Edward J. Bataillard of the Imperial College Healthcare National Health Service Trust, London, and colleagues.
To address this issue, the researchers conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. They found that greater than 80 years of age is an important cutoff for treating patients with a reduced R-CHOP dosage, according to their results, published in Blood Advances (2021;5[9]:2426-37).
Cutoff at 80 years of age
Their final review comprised 13 studies including 5,188 patients. Overall, the lower DI (intended or relative) was associated with inferior survival in seven of nine studies reporting crude survival analyses. In addition, most studies and those larger studies of higher quality showed poorer outcomes associated with reduced R-CHOP DI.
However, in subgroups of patients aged 80 years or more, survival was not consistently affected by the use of lower dosage R-CHOP, according to the researchers.
“We found evidence of improved survival with higher RDIs (up to R-CHOP-21) in those aged < 80 years, but the literature to date does not support full-dose intensity in those 80 years [or older],” they stated.
However, the researchers concluded that: “In the absence of improved options beyond R-CHOP in DLBCL over the past 20 years, prospective studies of DI are warranted, despite the recognized challenges involved.”
Two of the authors reported being previously employed by Roche. A third served as a consultant and adviser and received honoraria from Roche and other pharmaceutical companies. Several authors reported disclosures related to multiple other pharmaceutical companies.
Physicians often face the choice of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone + rituximab), according to Edward J. Bataillard of the Imperial College Healthcare National Health Service Trust, London, and colleagues.
To address this issue, the researchers conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. They found that greater than 80 years of age is an important cutoff for treating patients with a reduced R-CHOP dosage, according to their results, published in Blood Advances (2021;5[9]:2426-37).
Cutoff at 80 years of age
Their final review comprised 13 studies including 5,188 patients. Overall, the lower DI (intended or relative) was associated with inferior survival in seven of nine studies reporting crude survival analyses. In addition, most studies and those larger studies of higher quality showed poorer outcomes associated with reduced R-CHOP DI.
However, in subgroups of patients aged 80 years or more, survival was not consistently affected by the use of lower dosage R-CHOP, according to the researchers.
“We found evidence of improved survival with higher RDIs (up to R-CHOP-21) in those aged < 80 years, but the literature to date does not support full-dose intensity in those 80 years [or older],” they stated.
However, the researchers concluded that: “In the absence of improved options beyond R-CHOP in DLBCL over the past 20 years, prospective studies of DI are warranted, despite the recognized challenges involved.”
Two of the authors reported being previously employed by Roche. A third served as a consultant and adviser and received honoraria from Roche and other pharmaceutical companies. Several authors reported disclosures related to multiple other pharmaceutical companies.
Physicians often face the choice of whether to treat elderly patients with diffuse large B-cell lymphoma (DLBCL) with a full or reduced dose intensity (DI) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone + rituximab), according to Edward J. Bataillard of the Imperial College Healthcare National Health Service Trust, London, and colleagues.
To address this issue, the researchers conducted a systematic review assessing the impact of R-CHOP DI on DLBCL survival outcomes, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines. They found that greater than 80 years of age is an important cutoff for treating patients with a reduced R-CHOP dosage, according to their results, published in Blood Advances (2021;5[9]:2426-37).
Cutoff at 80 years of age
Their final review comprised 13 studies including 5,188 patients. Overall, the lower DI (intended or relative) was associated with inferior survival in seven of nine studies reporting crude survival analyses. In addition, most studies and those larger studies of higher quality showed poorer outcomes associated with reduced R-CHOP DI.
However, in subgroups of patients aged 80 years or more, survival was not consistently affected by the use of lower dosage R-CHOP, according to the researchers.
“We found evidence of improved survival with higher RDIs (up to R-CHOP-21) in those aged < 80 years, but the literature to date does not support full-dose intensity in those 80 years [or older],” they stated.
However, the researchers concluded that: “In the absence of improved options beyond R-CHOP in DLBCL over the past 20 years, prospective studies of DI are warranted, despite the recognized challenges involved.”
Two of the authors reported being previously employed by Roche. A third served as a consultant and adviser and received honoraria from Roche and other pharmaceutical companies. Several authors reported disclosures related to multiple other pharmaceutical companies.
FROM BLOOD ADVANCES