Levels of nicotine and marijuana vaping among adolescents remain elevated but did not increase significantly in the past year, data from the annual Monitoring the Future survey show.

The 2020 survey included responses from 11,821 individuals in 112 schools across the United States from Feb. 11, 2020, to March 14, 2020, at which time data collection ended prematurely because of the COVID-19 pandemic. The results represent approximately 25% of the usual data collection.

A key positive finding in this year’s survey was the relatively stable levels of nicotine vaping from 2019 to 2020, following a trend of notably increased use annually since vaping was added to the survey in 2017.

During the years 2017-2019, the percentage of teens who reported vaping nicotine in the past 12 months increased from 7.5% to 16.5% among 8th graders, from 15.8% to 30.7% among 10th graders, and from 18.8% to 35.3% among 12th graders. However, in 2020, the percentages of teens who reported past-year nicotine vaping were relatively steady at 16.6%, 30.7%, and 34.5%, for 8th-, 10th-, and 12th-grade students, respectively. In addition, reports of daily or near-daily nicotine vaping (defined as 20 occasions in the past 30 days) decreased significantly, from 6.8% to 3.6% among 10th graders and from 11.6% to 5.3% among 12th graders.

“The rapid rise of teen nicotine vaping in recent years has been unprecedented and deeply concerning since we know that nicotine is highly addictive and can be delivered at high doses by vaping devices, which may also contain other toxic chemicals that may be harmful when inhaled,” said Nora D. Volkow, MD, director of the National Institute on Drug Abuse in a press release accompanying the release of the findings. “It is encouraging to see a leveling off of this trend though the rates still remain very high.”

Reports of past-year marijuana vaping remained similar to 2019 levels after a twofold increase in the past 2 years, according to the survey. In early 2020, 8.1%, 19.1%, and 22.1% of 8th, 10th, and 12th graders reported past-year use. However, daily marijuana vaping decreased by more than half from 2019, to 1.1% among 10th graders and 1.5% among 12th graders.

Past-year use of the JUUL devices specifically also declined among older teens, from 28.7% in 2019 to 20% in 2020 among 10th graders and from 28.4% in 2019 to 22.7% in 2020 among 12th graders.

Other trends this year included the increased past-year use of amphetamines, inhalants, and cough medicines among 8th graders, and relatively low reported use among 12th graders of LSD (3.9%), synthetic cannabinoids (2.4%), cocaine (2.9%), ecstasy (1.8%), methamphetamine (1.4%), and heroin (0.3%).

The findings were published in JAMA Pediatrics.

 

Early data show progress

“The MTF survey is the most referenced and reliable longitudinal study reporting current use of tobacco, drugs, and alcohol among young people,” said Mark S. Gold, MD, of Washington University, St. Louis, in an interview.

“The new data, collected before data collection stopped prematurely due to the COVID-19 pandemic, suggests that some progress is being made in slowing the increase in substance use among these, the most vulnerable,” he said.

“The best news was that nicotine vaping decreased significantly after its meteoric increase over the past few years,” Dr. Gold emphasized. “Past-year vaping of marijuana remained steady at alarming levels in 2020, with 8.1% of 8th graders, 19.1% of 10th graders, and 22.1% of 12th graders reporting past-year use, following a two-fold increase over the past 2 years.” The use of all forms of marijuana, including smoking and vaping, did not significantly change in any of the three grades for lifetime use, past 12-month use, past 30-day use, and daily use from 2019 to 2020.

“Teen alcohol use has not significantly changed over the past 5 years,” and cigarette smoking in the last 30 days did not significantly change from 2019 to 2020, said Dr. Gold. However, “as with adults, psychostimulant use is increasing. Past year nonmedical use of amphetamines among 8th graders increased, from 3.5% in 2017 to 5.3% in 2020.”
 

COVID-era limitations

“The data suggest that pre-COVID pandemic vaping, smoking cigarettes, marijuana, and alcohol use had stabilized,” Dr. Gold said. “However, it is very difficult to predict what the COVID era data will show as many young people are at home, on the streets, and unsupervised; while adult substance misuse, substance use disorders, and overdoses are increasing. Drug supplies and access have increased for alcohol, cannabis, vaping, and tobacco as have supply synthetics like methamphetamine and fentanyl.”

In addition, “access to evaluation, intervention, and treatment have been curtailed during the pandemic,” Dr. Gold said. “The loss of peer role models, daily routine, and teacher or other adult supervision and interventions may interact with increasing despair, social isolation, depression, and anxiety in ways that are unknown. “It will not be clear until the next survey if perceived dangerousness has changed in ways that can protect these 8th, 10th, and 12th graders and increase the numbers of never users or current nonusers.”

The Monitoring the Future survey is conducted each year by the University of Michigan’s Institute for Social Research, Ann Arbor, and supported by NIDA, part of the National Institutes of Health. Dr. Gold had no relevant financial conflicts to disclose.

Levels of nicotine and marijuana vaping among adolescents remain elevated but did not increase significantly in the past year, data from the annual Monitoring the Future survey show.

The 2020 survey included responses from 11,821 individuals in 112 schools across the United States from Feb. 11, 2020, to March 14, 2020, at which time data collection ended prematurely because of the COVID-19 pandemic. The results represent approximately 25% of the usual data collection.

A key positive finding in this year’s survey was the relatively stable levels of nicotine vaping from 2019 to 2020, following a trend of notably increased use annually since vaping was added to the survey in 2017.

During the years 2017-2019, the percentage of teens who reported vaping nicotine in the past 12 months increased from 7.5% to 16.5% among 8th graders, from 15.8% to 30.7% among 10th graders, and from 18.8% to 35.3% among 12th graders. However, in 2020, the percentages of teens who reported past-year nicotine vaping were relatively steady at 16.6%, 30.7%, and 34.5%, for 8th-, 10th-, and 12th-grade students, respectively. In addition, reports of daily or near-daily nicotine vaping (defined as 20 occasions in the past 30 days) decreased significantly, from 6.8% to 3.6% among 10th graders and from 11.6% to 5.3% among 12th graders.

“The rapid rise of teen nicotine vaping in recent years has been unprecedented and deeply concerning since we know that nicotine is highly addictive and can be delivered at high doses by vaping devices, which may also contain other toxic chemicals that may be harmful when inhaled,” said Nora D. Volkow, MD, director of the National Institute on Drug Abuse in a press release accompanying the release of the findings. “It is encouraging to see a leveling off of this trend though the rates still remain very high.”

Reports of past-year marijuana vaping remained similar to 2019 levels after a twofold increase in the past 2 years, according to the survey. In early 2020, 8.1%, 19.1%, and 22.1% of 8th, 10th, and 12th graders reported past-year use. However, daily marijuana vaping decreased by more than half from 2019, to 1.1% among 10th graders and 1.5% among 12th graders.

Past-year use of the JUUL devices specifically also declined among older teens, from 28.7% in 2019 to 20% in 2020 among 10th graders and from 28.4% in 2019 to 22.7% in 2020 among 12th graders.

Other trends this year included the increased past-year use of amphetamines, inhalants, and cough medicines among 8th graders, and relatively low reported use among 12th graders of LSD (3.9%), synthetic cannabinoids (2.4%), cocaine (2.9%), ecstasy (1.8%), methamphetamine (1.4%), and heroin (0.3%).

The findings were published in JAMA Pediatrics.

 

Early data show progress

“The MTF survey is the most referenced and reliable longitudinal study reporting current use of tobacco, drugs, and alcohol among young people,” said Mark S. Gold, MD, of Washington University, St. Louis, in an interview.

“The new data, collected before data collection stopped prematurely due to the COVID-19 pandemic, suggests that some progress is being made in slowing the increase in substance use among these, the most vulnerable,” he said.

“The best news was that nicotine vaping decreased significantly after its meteoric increase over the past few years,” Dr. Gold emphasized. “Past-year vaping of marijuana remained steady at alarming levels in 2020, with 8.1% of 8th graders, 19.1% of 10th graders, and 22.1% of 12th graders reporting past-year use, following a two-fold increase over the past 2 years.” The use of all forms of marijuana, including smoking and vaping, did not significantly change in any of the three grades for lifetime use, past 12-month use, past 30-day use, and daily use from 2019 to 2020.

“Teen alcohol use has not significantly changed over the past 5 years,” and cigarette smoking in the last 30 days did not significantly change from 2019 to 2020, said Dr. Gold. However, “as with adults, psychostimulant use is increasing. Past year nonmedical use of amphetamines among 8th graders increased, from 3.5% in 2017 to 5.3% in 2020.”
 

COVID-era limitations

“The data suggest that pre-COVID pandemic vaping, smoking cigarettes, marijuana, and alcohol use had stabilized,” Dr. Gold said. “However, it is very difficult to predict what the COVID era data will show as many young people are at home, on the streets, and unsupervised; while adult substance misuse, substance use disorders, and overdoses are increasing. Drug supplies and access have increased for alcohol, cannabis, vaping, and tobacco as have supply synthetics like methamphetamine and fentanyl.”

In addition, “access to evaluation, intervention, and treatment have been curtailed during the pandemic,” Dr. Gold said. “The loss of peer role models, daily routine, and teacher or other adult supervision and interventions may interact with increasing despair, social isolation, depression, and anxiety in ways that are unknown. “It will not be clear until the next survey if perceived dangerousness has changed in ways that can protect these 8th, 10th, and 12th graders and increase the numbers of never users or current nonusers.”

The Monitoring the Future survey is conducted each year by the University of Michigan’s Institute for Social Research, Ann Arbor, and supported by NIDA, part of the National Institutes of Health. Dr. Gold had no relevant financial conflicts to disclose.

Levels of nicotine and marijuana vaping among adolescents remain elevated but did not increase significantly in the past year, data from the annual Monitoring the Future survey show.

The 2020 survey included responses from 11,821 individuals in 112 schools across the United States from Feb. 11, 2020, to March 14, 2020, at which time data collection ended prematurely because of the COVID-19 pandemic. The results represent approximately 25% of the usual data collection.

A key positive finding in this year’s survey was the relatively stable levels of nicotine vaping from 2019 to 2020, following a trend of notably increased use annually since vaping was added to the survey in 2017.

During the years 2017-2019, the percentage of teens who reported vaping nicotine in the past 12 months increased from 7.5% to 16.5% among 8th graders, from 15.8% to 30.7% among 10th graders, and from 18.8% to 35.3% among 12th graders. However, in 2020, the percentages of teens who reported past-year nicotine vaping were relatively steady at 16.6%, 30.7%, and 34.5%, for 8th-, 10th-, and 12th-grade students, respectively. In addition, reports of daily or near-daily nicotine vaping (defined as 20 occasions in the past 30 days) decreased significantly, from 6.8% to 3.6% among 10th graders and from 11.6% to 5.3% among 12th graders.

“The rapid rise of teen nicotine vaping in recent years has been unprecedented and deeply concerning since we know that nicotine is highly addictive and can be delivered at high doses by vaping devices, which may also contain other toxic chemicals that may be harmful when inhaled,” said Nora D. Volkow, MD, director of the National Institute on Drug Abuse in a press release accompanying the release of the findings. “It is encouraging to see a leveling off of this trend though the rates still remain very high.”

Reports of past-year marijuana vaping remained similar to 2019 levels after a twofold increase in the past 2 years, according to the survey. In early 2020, 8.1%, 19.1%, and 22.1% of 8th, 10th, and 12th graders reported past-year use. However, daily marijuana vaping decreased by more than half from 2019, to 1.1% among 10th graders and 1.5% among 12th graders.

Past-year use of the JUUL devices specifically also declined among older teens, from 28.7% in 2019 to 20% in 2020 among 10th graders and from 28.4% in 2019 to 22.7% in 2020 among 12th graders.

Other trends this year included the increased past-year use of amphetamines, inhalants, and cough medicines among 8th graders, and relatively low reported use among 12th graders of LSD (3.9%), synthetic cannabinoids (2.4%), cocaine (2.9%), ecstasy (1.8%), methamphetamine (1.4%), and heroin (0.3%).

The findings were published in JAMA Pediatrics.

 

Early data show progress

“The MTF survey is the most referenced and reliable longitudinal study reporting current use of tobacco, drugs, and alcohol among young people,” said Mark S. Gold, MD, of Washington University, St. Louis, in an interview.

“The new data, collected before data collection stopped prematurely due to the COVID-19 pandemic, suggests that some progress is being made in slowing the increase in substance use among these, the most vulnerable,” he said.

“The best news was that nicotine vaping decreased significantly after its meteoric increase over the past few years,” Dr. Gold emphasized. “Past-year vaping of marijuana remained steady at alarming levels in 2020, with 8.1% of 8th graders, 19.1% of 10th graders, and 22.1% of 12th graders reporting past-year use, following a two-fold increase over the past 2 years.” The use of all forms of marijuana, including smoking and vaping, did not significantly change in any of the three grades for lifetime use, past 12-month use, past 30-day use, and daily use from 2019 to 2020.

“Teen alcohol use has not significantly changed over the past 5 years,” and cigarette smoking in the last 30 days did not significantly change from 2019 to 2020, said Dr. Gold. However, “as with adults, psychostimulant use is increasing. Past year nonmedical use of amphetamines among 8th graders increased, from 3.5% in 2017 to 5.3% in 2020.”
 

COVID-era limitations

“The data suggest that pre-COVID pandemic vaping, smoking cigarettes, marijuana, and alcohol use had stabilized,” Dr. Gold said. “However, it is very difficult to predict what the COVID era data will show as many young people are at home, on the streets, and unsupervised; while adult substance misuse, substance use disorders, and overdoses are increasing. Drug supplies and access have increased for alcohol, cannabis, vaping, and tobacco as have supply synthetics like methamphetamine and fentanyl.”

In addition, “access to evaluation, intervention, and treatment have been curtailed during the pandemic,” Dr. Gold said. “The loss of peer role models, daily routine, and teacher or other adult supervision and interventions may interact with increasing despair, social isolation, depression, and anxiety in ways that are unknown. “It will not be clear until the next survey if perceived dangerousness has changed in ways that can protect these 8th, 10th, and 12th graders and increase the numbers of never users or current nonusers.”

The Monitoring the Future survey is conducted each year by the University of Michigan’s Institute for Social Research, Ann Arbor, and supported by NIDA, part of the National Institutes of Health. Dr. Gold had no relevant financial conflicts to disclose.

Sleep medications for older patients who report sleep problems may not be the best treatment given growing evidence of the link between these medications and the risk of incident dementia.

Adults aged 65 years and older who used sleep medications 5-7 days a week demonstrated a 30% increased risk of dementia, compared with those who did not use sleep medications, findings from a prospective study of 6,373 individuals show.

Adults aged 65 and older report a higher burden of sleep problems than other age groups, but major medical associations discourage the use of sleep medications by older adults because of growing evidence of a link between sleep medication use and cognitive decline, wrote Rebecca Robbins, MD, of Brigham and Women’s Hospital, Boston, and colleagues. However, data on this association among adults in the United States are limited, they said.

In a study published in Sleep Medicine, the researchers surveyed 6,373 adults aged 65 years and older who were enrolled in the nationally representative National Health and Aging Trends Study (NHATS). The majority of the participants were non-Hispanic White (71%), 59% were women, and 21% ranged in age from 70 to 74 years.

Participants responded to questions about routine sleep medication use. Routine was defined as “most nights” or “every night.” The data were collected for an 8-year period from 2011 to 2018. The study began in 2011, with a core interview administered annually.

Approximately 15% of the study population reported routine use of sleep medications. Overall, routine use of sleep medication was significantly associated with risk of incident dementia (hazard ratio, 1.30; P < .01) after controlling for multiple variables including age, sex, education level, and chronic conditions.

Dementia screening was conducted by participants rating their memory and then performing a memory-related activity (immediate and delayed 10-word recall) and other exercises to assess executive function and orientation. A separate eight-item informant screener was performed for patient proxies. The researcher noted, “Sensitivity of the NHATS probable dementia screening measure has been determined in previous research to be 66%, and specificity is 87%, with respect to a clinical dementia diagnosis.”

The study findings were limited by several factors including the use of self-reports, the lack of data on type or dose of sleep medication, and lack of data on the indication for the prescription, the researchers noted.

“Also, sleep medication use leads to worse performance on cognitive testing, such as the questionnaires used to screen for dementia in this study, and therefore could have resulted in a false diagnosis of dementia,” they added.

However, the results were strengthened by the large, nationally representative study population and support the need for quality geriatric care, the researchers said.

“Our findings provide further support and evidence that sleep medications are all too commonly administered, yet associated with greater risk for incident dementia, and that the U.S. health care system is in need of creative solutions for addressing poor sleep among older individuals,” they concluded.
 

Implications and alternatives

The study is important as the number of aging Americans increases, said Carolyn M. D’Ambrosio, MD, FCCP, of Brigham and Women’s Hospital and Harvard Medical School, Boston, in an interview. “In the elderly, inability to fall asleep or stay asleep are common issues that are brought to a health care provider,” she said. Dr. D’Ambrosio said she was not surprised by the study findings “as elderly patients often have sleep issues and sometimes a well-meaning health care provider gives them sleep medication to help. We have known that some of these sleep medications such as benzodiazepines affect cognitive performance,” she said.

Dr. D’Ambrosio said she avoids prescribing sleep medications for older adults if possible. “A deep dive into sleep habits, environment, and other things that disrupt sleep often gets to the problem rather than just masking it with a sleep medication,” she noted. Alternatives to improve sleep in older adults include exercise, exposure to bright light during the day, and good healthy sleep habits, all of which contribute to improved sleep in the elderly, said Dr. D’Ambrosio. She also recommends screening older adults for other issues that affect sleep, such as chronic pain.

The current study highlighted the association between sleep medication use and dementia, but it does not show causation, Dr. D’Ambrosio said. “So much more needs to be done to determine whether the sleep medications are causing worsening cognitive function long term, or if the dementia is starting but not yet diagnosed and the sleep medication is given but not the cause of the dementia, she noted.
 

Research gaps and treatment strategies

Older adults experiencing sleep difficulties may try various medications including pharmacologics (e.g., benzodiazepines), over-the-counter agents, such as diphenhydramine or doxylamine preparations, and/or herbal and nutritional supplements such as valerian or melatonin, said Mary Jo S. Farmer, MD, FCCP, of the University of Massachusetts Medical School–Baystate, Springfield, in an interview. “However, sleep medications, particularly benzodiazepines, are strongly discouraged by major medical associations including the American Geriatrics Society in part because of the growing evidence that use of sleep medications is associated with cognitive impairment and decline,” she said.

The current study results contribute to previous work demonstrating that both pharmacologic and nonpharmacologic sleep medication, although commonly administered, is associated with subsequent adverse outcomes in older adults, Dr. Farmer said. This association sets the stage for creative and different solutions for addressing poor sleep among older adults, such as behavioral treatments including cognitive-behavioral therapy, she noted.

Dr. Farmer said, “Areas for future research include exploring the causal link between prescription and/or over-the-counter sleep medication use and incident dementia in a randomized controlled trial,” she added.

“Another interesting opportunity for future research is to explore the indications for sleep medications among older adults since it has been shown in the general population that sleep difficulties represent only 12% of the indication for sleep medication prescriptions,” Dr. Farmer noted. “Future research could examine the strength of the underlying motivation to use sleep medication even in light of suggested long-term effects, and the effectiveness of other measures to avoid or minimize sleep difficulties,” she said.

“My experience is that the majority of ambulatory patients recently seen in sleep clinic want to avoid long-term use of sleep medications and will ask what other measures can be tried to consistently achieve a good night’s sleep without medication use,” Dr. Farmer said. “If medications are used, patients would rather try melatonin than a benzodiazepine. Many patients who come to sleep clinic with sleep medications already prescribed and are subsequently found to have sleep apnea and/or restless legs find that they no longer need sleep medication when these other medical conditions are appropriately diagnosed and managed,” she explained. “Finally, many patients tell me they feel less energetic upon awakening, almost feel hung over, and express being less sharp cognitively when taking pharmacologic sleep medication, whether for short or long periods of time, and therefore they want to avoid continuing with sleep medication use,” she said.

Dr. Farmer’s strategy for developing alternatives to sleep medications in older adults includes taking a careful history, including a complete list of medical problems, review of medications, and a thorough sleep history including usual time of sleep onset, awake time, and the frequency of daytime naps. “Tips for improving the quality of nighttime sleep may include adequately treating pain and other medical conditions such as heartburn, sleep apnea, and restless legs, creating a soothing environment to promote sleep by eliminating noise and bright lights, avoiding stimulant medications and substances such as caffeine and nicotine before bedtime, avoiding excessive amounts of alcohol, avoiding diuretics before bedtime, encouraging physical activity during the day, spending time in the sunlight as much as possible to help regulate the sleep cycle, limiting daytime naps, and establishing a regular sleep schedule,” she said.

The study was supported by National Institutes of Health awards K01HL150339, U54MD000538, K07AG052685, R01AG056531, R01AG056031. Lead author Dr. Robbins had no financial conflicts to disclose. Dr. D’Ambrosio disclosed serving as a section editor for sleep medicine for Dynamed and owning a patent on a circadian programming device. Dr. Farmer had no disclosures.

SOURCE: Robbins R et al. Sleep Med. 2020 Nov 11. doi: 10.1016/j.sleep.2020.11.004.

Sleep medications for older patients who report sleep problems may not be the best treatment given growing evidence of the link between these medications and the risk of incident dementia.

Adults aged 65 years and older who used sleep medications 5-7 days a week demonstrated a 30% increased risk of dementia, compared with those who did not use sleep medications, findings from a prospective study of 6,373 individuals show.

Adults aged 65 and older report a higher burden of sleep problems than other age groups, but major medical associations discourage the use of sleep medications by older adults because of growing evidence of a link between sleep medication use and cognitive decline, wrote Rebecca Robbins, MD, of Brigham and Women’s Hospital, Boston, and colleagues. However, data on this association among adults in the United States are limited, they said.

In a study published in Sleep Medicine, the researchers surveyed 6,373 adults aged 65 years and older who were enrolled in the nationally representative National Health and Aging Trends Study (NHATS). The majority of the participants were non-Hispanic White (71%), 59% were women, and 21% ranged in age from 70 to 74 years.

Participants responded to questions about routine sleep medication use. Routine was defined as “most nights” or “every night.” The data were collected for an 8-year period from 2011 to 2018. The study began in 2011, with a core interview administered annually.

Approximately 15% of the study population reported routine use of sleep medications. Overall, routine use of sleep medication was significantly associated with risk of incident dementia (hazard ratio, 1.30; P < .01) after controlling for multiple variables including age, sex, education level, and chronic conditions.

Dementia screening was conducted by participants rating their memory and then performing a memory-related activity (immediate and delayed 10-word recall) and other exercises to assess executive function and orientation. A separate eight-item informant screener was performed for patient proxies. The researcher noted, “Sensitivity of the NHATS probable dementia screening measure has been determined in previous research to be 66%, and specificity is 87%, with respect to a clinical dementia diagnosis.”

The study findings were limited by several factors including the use of self-reports, the lack of data on type or dose of sleep medication, and lack of data on the indication for the prescription, the researchers noted.

“Also, sleep medication use leads to worse performance on cognitive testing, such as the questionnaires used to screen for dementia in this study, and therefore could have resulted in a false diagnosis of dementia,” they added.

However, the results were strengthened by the large, nationally representative study population and support the need for quality geriatric care, the researchers said.

“Our findings provide further support and evidence that sleep medications are all too commonly administered, yet associated with greater risk for incident dementia, and that the U.S. health care system is in need of creative solutions for addressing poor sleep among older individuals,” they concluded.
 

Implications and alternatives

The study is important as the number of aging Americans increases, said Carolyn M. D’Ambrosio, MD, FCCP, of Brigham and Women’s Hospital and Harvard Medical School, Boston, in an interview. “In the elderly, inability to fall asleep or stay asleep are common issues that are brought to a health care provider,” she said. Dr. D’Ambrosio said she was not surprised by the study findings “as elderly patients often have sleep issues and sometimes a well-meaning health care provider gives them sleep medication to help. We have known that some of these sleep medications such as benzodiazepines affect cognitive performance,” she said.

Dr. D’Ambrosio said she avoids prescribing sleep medications for older adults if possible. “A deep dive into sleep habits, environment, and other things that disrupt sleep often gets to the problem rather than just masking it with a sleep medication,” she noted. Alternatives to improve sleep in older adults include exercise, exposure to bright light during the day, and good healthy sleep habits, all of which contribute to improved sleep in the elderly, said Dr. D’Ambrosio. She also recommends screening older adults for other issues that affect sleep, such as chronic pain.

The current study highlighted the association between sleep medication use and dementia, but it does not show causation, Dr. D’Ambrosio said. “So much more needs to be done to determine whether the sleep medications are causing worsening cognitive function long term, or if the dementia is starting but not yet diagnosed and the sleep medication is given but not the cause of the dementia, she noted.
 

Research gaps and treatment strategies

Older adults experiencing sleep difficulties may try various medications including pharmacologics (e.g., benzodiazepines), over-the-counter agents, such as diphenhydramine or doxylamine preparations, and/or herbal and nutritional supplements such as valerian or melatonin, said Mary Jo S. Farmer, MD, FCCP, of the University of Massachusetts Medical School–Baystate, Springfield, in an interview. “However, sleep medications, particularly benzodiazepines, are strongly discouraged by major medical associations including the American Geriatrics Society in part because of the growing evidence that use of sleep medications is associated with cognitive impairment and decline,” she said.

The current study results contribute to previous work demonstrating that both pharmacologic and nonpharmacologic sleep medication, although commonly administered, is associated with subsequent adverse outcomes in older adults, Dr. Farmer said. This association sets the stage for creative and different solutions for addressing poor sleep among older adults, such as behavioral treatments including cognitive-behavioral therapy, she noted.

Dr. Farmer said, “Areas for future research include exploring the causal link between prescription and/or over-the-counter sleep medication use and incident dementia in a randomized controlled trial,” she added.

“Another interesting opportunity for future research is to explore the indications for sleep medications among older adults since it has been shown in the general population that sleep difficulties represent only 12% of the indication for sleep medication prescriptions,” Dr. Farmer noted. “Future research could examine the strength of the underlying motivation to use sleep medication even in light of suggested long-term effects, and the effectiveness of other measures to avoid or minimize sleep difficulties,” she said.

“My experience is that the majority of ambulatory patients recently seen in sleep clinic want to avoid long-term use of sleep medications and will ask what other measures can be tried to consistently achieve a good night’s sleep without medication use,” Dr. Farmer said. “If medications are used, patients would rather try melatonin than a benzodiazepine. Many patients who come to sleep clinic with sleep medications already prescribed and are subsequently found to have sleep apnea and/or restless legs find that they no longer need sleep medication when these other medical conditions are appropriately diagnosed and managed,” she explained. “Finally, many patients tell me they feel less energetic upon awakening, almost feel hung over, and express being less sharp cognitively when taking pharmacologic sleep medication, whether for short or long periods of time, and therefore they want to avoid continuing with sleep medication use,” she said.

Dr. Farmer’s strategy for developing alternatives to sleep medications in older adults includes taking a careful history, including a complete list of medical problems, review of medications, and a thorough sleep history including usual time of sleep onset, awake time, and the frequency of daytime naps. “Tips for improving the quality of nighttime sleep may include adequately treating pain and other medical conditions such as heartburn, sleep apnea, and restless legs, creating a soothing environment to promote sleep by eliminating noise and bright lights, avoiding stimulant medications and substances such as caffeine and nicotine before bedtime, avoiding excessive amounts of alcohol, avoiding diuretics before bedtime, encouraging physical activity during the day, spending time in the sunlight as much as possible to help regulate the sleep cycle, limiting daytime naps, and establishing a regular sleep schedule,” she said.

The study was supported by National Institutes of Health awards K01HL150339, U54MD000538, K07AG052685, R01AG056531, R01AG056031. Lead author Dr. Robbins had no financial conflicts to disclose. Dr. D’Ambrosio disclosed serving as a section editor for sleep medicine for Dynamed and owning a patent on a circadian programming device. Dr. Farmer had no disclosures.

SOURCE: Robbins R et al. Sleep Med. 2020 Nov 11. doi: 10.1016/j.sleep.2020.11.004.

Sleep medications for older patients who report sleep problems may not be the best treatment given growing evidence of the link between these medications and the risk of incident dementia.

Adults aged 65 years and older who used sleep medications 5-7 days a week demonstrated a 30% increased risk of dementia, compared with those who did not use sleep medications, findings from a prospective study of 6,373 individuals show.

Adults aged 65 and older report a higher burden of sleep problems than other age groups, but major medical associations discourage the use of sleep medications by older adults because of growing evidence of a link between sleep medication use and cognitive decline, wrote Rebecca Robbins, MD, of Brigham and Women’s Hospital, Boston, and colleagues. However, data on this association among adults in the United States are limited, they said.

In a study published in Sleep Medicine, the researchers surveyed 6,373 adults aged 65 years and older who were enrolled in the nationally representative National Health and Aging Trends Study (NHATS). The majority of the participants were non-Hispanic White (71%), 59% were women, and 21% ranged in age from 70 to 74 years.

Participants responded to questions about routine sleep medication use. Routine was defined as “most nights” or “every night.” The data were collected for an 8-year period from 2011 to 2018. The study began in 2011, with a core interview administered annually.

Approximately 15% of the study population reported routine use of sleep medications. Overall, routine use of sleep medication was significantly associated with risk of incident dementia (hazard ratio, 1.30; P < .01) after controlling for multiple variables including age, sex, education level, and chronic conditions.

Dementia screening was conducted by participants rating their memory and then performing a memory-related activity (immediate and delayed 10-word recall) and other exercises to assess executive function and orientation. A separate eight-item informant screener was performed for patient proxies. The researcher noted, “Sensitivity of the NHATS probable dementia screening measure has been determined in previous research to be 66%, and specificity is 87%, with respect to a clinical dementia diagnosis.”

The study findings were limited by several factors including the use of self-reports, the lack of data on type or dose of sleep medication, and lack of data on the indication for the prescription, the researchers noted.

“Also, sleep medication use leads to worse performance on cognitive testing, such as the questionnaires used to screen for dementia in this study, and therefore could have resulted in a false diagnosis of dementia,” they added.

However, the results were strengthened by the large, nationally representative study population and support the need for quality geriatric care, the researchers said.

“Our findings provide further support and evidence that sleep medications are all too commonly administered, yet associated with greater risk for incident dementia, and that the U.S. health care system is in need of creative solutions for addressing poor sleep among older individuals,” they concluded.
 

Implications and alternatives

The study is important as the number of aging Americans increases, said Carolyn M. D’Ambrosio, MD, FCCP, of Brigham and Women’s Hospital and Harvard Medical School, Boston, in an interview. “In the elderly, inability to fall asleep or stay asleep are common issues that are brought to a health care provider,” she said. Dr. D’Ambrosio said she was not surprised by the study findings “as elderly patients often have sleep issues and sometimes a well-meaning health care provider gives them sleep medication to help. We have known that some of these sleep medications such as benzodiazepines affect cognitive performance,” she said.

Dr. D’Ambrosio said she avoids prescribing sleep medications for older adults if possible. “A deep dive into sleep habits, environment, and other things that disrupt sleep often gets to the problem rather than just masking it with a sleep medication,” she noted. Alternatives to improve sleep in older adults include exercise, exposure to bright light during the day, and good healthy sleep habits, all of which contribute to improved sleep in the elderly, said Dr. D’Ambrosio. She also recommends screening older adults for other issues that affect sleep, such as chronic pain.

The current study highlighted the association between sleep medication use and dementia, but it does not show causation, Dr. D’Ambrosio said. “So much more needs to be done to determine whether the sleep medications are causing worsening cognitive function long term, or if the dementia is starting but not yet diagnosed and the sleep medication is given but not the cause of the dementia, she noted.
 

Research gaps and treatment strategies

Older adults experiencing sleep difficulties may try various medications including pharmacologics (e.g., benzodiazepines), over-the-counter agents, such as diphenhydramine or doxylamine preparations, and/or herbal and nutritional supplements such as valerian or melatonin, said Mary Jo S. Farmer, MD, FCCP, of the University of Massachusetts Medical School–Baystate, Springfield, in an interview. “However, sleep medications, particularly benzodiazepines, are strongly discouraged by major medical associations including the American Geriatrics Society in part because of the growing evidence that use of sleep medications is associated with cognitive impairment and decline,” she said.

The current study results contribute to previous work demonstrating that both pharmacologic and nonpharmacologic sleep medication, although commonly administered, is associated with subsequent adverse outcomes in older adults, Dr. Farmer said. This association sets the stage for creative and different solutions for addressing poor sleep among older adults, such as behavioral treatments including cognitive-behavioral therapy, she noted.

Dr. Farmer said, “Areas for future research include exploring the causal link between prescription and/or over-the-counter sleep medication use and incident dementia in a randomized controlled trial,” she added.

“Another interesting opportunity for future research is to explore the indications for sleep medications among older adults since it has been shown in the general population that sleep difficulties represent only 12% of the indication for sleep medication prescriptions,” Dr. Farmer noted. “Future research could examine the strength of the underlying motivation to use sleep medication even in light of suggested long-term effects, and the effectiveness of other measures to avoid or minimize sleep difficulties,” she said.

“My experience is that the majority of ambulatory patients recently seen in sleep clinic want to avoid long-term use of sleep medications and will ask what other measures can be tried to consistently achieve a good night’s sleep without medication use,” Dr. Farmer said. “If medications are used, patients would rather try melatonin than a benzodiazepine. Many patients who come to sleep clinic with sleep medications already prescribed and are subsequently found to have sleep apnea and/or restless legs find that they no longer need sleep medication when these other medical conditions are appropriately diagnosed and managed,” she explained. “Finally, many patients tell me they feel less energetic upon awakening, almost feel hung over, and express being less sharp cognitively when taking pharmacologic sleep medication, whether for short or long periods of time, and therefore they want to avoid continuing with sleep medication use,” she said.

Dr. Farmer’s strategy for developing alternatives to sleep medications in older adults includes taking a careful history, including a complete list of medical problems, review of medications, and a thorough sleep history including usual time of sleep onset, awake time, and the frequency of daytime naps. “Tips for improving the quality of nighttime sleep may include adequately treating pain and other medical conditions such as heartburn, sleep apnea, and restless legs, creating a soothing environment to promote sleep by eliminating noise and bright lights, avoiding stimulant medications and substances such as caffeine and nicotine before bedtime, avoiding excessive amounts of alcohol, avoiding diuretics before bedtime, encouraging physical activity during the day, spending time in the sunlight as much as possible to help regulate the sleep cycle, limiting daytime naps, and establishing a regular sleep schedule,” she said.

The study was supported by National Institutes of Health awards K01HL150339, U54MD000538, K07AG052685, R01AG056531, R01AG056031. Lead author Dr. Robbins had no financial conflicts to disclose. Dr. D’Ambrosio disclosed serving as a section editor for sleep medicine for Dynamed and owning a patent on a circadian programming device. Dr. Farmer had no disclosures.

SOURCE: Robbins R et al. Sleep Med. 2020 Nov 11. doi: 10.1016/j.sleep.2020.11.004.

Federal advisers on December 17 overwhelmingly recommended an emergency clearance to Moderna Inc’s COVID-19 vaccine, while noting concerns about potential allergic reactions and the challenges of continuing testing of this medicine.

The US Food and Drug Administration (FDA) put Moderna’s application before its Vaccines and Related Biological Products Advisory Committee. The panel voted 20-0 on this question: “Based on the totality of scientific evidence available, do the benefits of the Moderna COVID-19 Vaccine outweigh its risks for use in individuals 18 years of age and older?” There was one abstention.

The FDA is not bound to act on the recommendations of its advisers, but the agency usually takes the panel’s advice. The FDA cleared the similar Pfizer-BioNTech vaccine on December 11 through an emergency use authorization (EUA), following a positive vote for the product at a December 10 advisory committee meeting. In this case, the FDA staff appeared to be pushing for a broad endorsement of the Moderna vaccine, for which the agency appears likely to soon also grant an EUA.

Marion Gruber, PhD, director of the Office of Vaccines Research and Review at FDA’s Center for Biologics Evaluation and Research, earlier rebuffed attempts by some of the panelists to alter the voting question. Some panelists wanted to make tweaks, including a rephrasing to underscore the limited nature of an EUA, compared with a more complete approval through the biologics license application (BLA) process.

FDA panelist Michael Kurilla, MD, PhD, of the National Institutes of Health was the only panelist to abstain from voting. He said he was uncomfortable with the phrasing of the question.

“In the midst of a pandemic and with limited vaccine supply available, a blanket statement for individuals 18 years and older is just too broad,” he said. “I’m not convinced that for all of those age groups the benefits do actually outweigh the risks.”

In general, though, there was strong support for Moderna’s vaccine. FDA panelist James Hildreth Sr, MD, PhD, of Meharry Medical College in Nashville, Tennessee spoke of the “remarkable achievement” seen in having two vaccines ready for clearance by December for a virus that only emerged as a threat this year.

Study data indicate the primary efficacy endpoint demonstrated vaccine efficacy (VE) of 94.1% (95% CI, 89.3% - 96.8%) for the Moderna vaccine, with 11 COVID-19 cases in the vaccine group and 185 COVID-19 cases in the placebo group, the FDA staff noted during the meeting.

The advisers and FDA staff also honed in on several key issues with COVID-19 vaccines, including the challenge of having people in the placebo groups of studies seek to get cleared vaccines. Also of concern to the panel were early reports of allergic reactions seen with the Pfizer product.

Doran L. Fink, MD, PhD, an FDA official who has been closely involved with the COVID-19 vaccines, told the panel that two healthcare workers in Alaska had allergic reactions minutes after receiving the Pfizer vaccine, one of which was a case of anaphylactic reaction that resulted in hospitalization.

In the United Kingdom, there were two cases reported of notable allergic reactions, leading regulators there to issue a warning that people who have a history of significant allergic reactions should not currently receive the Pfizer-BioNTech vaccine.

The people involved in these incidents have recovered or are recovering, Fink said. But the FDA expects there will be additional reports of allergic reactions to COVID-19 vaccines.

“These cases underscores the need to remain vigilant during the early phase of the vaccination campaign,” Fink said. “To this end, FDA is working with Pfizer to further revise factsheets and prescribing information for their vaccine to draw attention to CDC guidelines for post- vaccination monitoring and management of immediate allergic reactions.”

mRNA vaccines in the lead

An FDA emergency clearance for Moderna’s product would be another vote of confidence in a new approach to making vaccines. Both the Pfizer-BioNTech and Moderna vaccines provide the immune system with a kind of blueprint in the form of genetic material, mRNA. The mRNA sets the stage for the synthesis of the signature spike protein that the SARS-CoV-2 virus uses to attach to and infect human cells.

In a December 15 commentary for this news organization Michael E. Pichichero, MD, wrote that the “revolutionary aspect of mRNA vaccines is the speed at which they can be designed and produced.”

“This is why they lead the pack among the SARS-CoV-2 vaccine candidates and why the National Institute of Allergy and Infectious Diseases provided financial, technical, and/or clinical support. Indeed, once the amino acid sequence of a protein can be determined (a relatively easy task these days) it’s straightforward to synthesize mRNA in the lab — and it can be done incredibly fast,” he wrote.

The FDA allowed one waiver for panelist James K. Hildreth in connection with his personal relationship to a trial participant and his university’s participation in vaccine testing.

This article first appeared on Medscape.com.

Federal advisers on December 17 overwhelmingly recommended an emergency clearance to Moderna Inc’s COVID-19 vaccine, while noting concerns about potential allergic reactions and the challenges of continuing testing of this medicine.

The US Food and Drug Administration (FDA) put Moderna’s application before its Vaccines and Related Biological Products Advisory Committee. The panel voted 20-0 on this question: “Based on the totality of scientific evidence available, do the benefits of the Moderna COVID-19 Vaccine outweigh its risks for use in individuals 18 years of age and older?” There was one abstention.

The FDA is not bound to act on the recommendations of its advisers, but the agency usually takes the panel’s advice. The FDA cleared the similar Pfizer-BioNTech vaccine on December 11 through an emergency use authorization (EUA), following a positive vote for the product at a December 10 advisory committee meeting. In this case, the FDA staff appeared to be pushing for a broad endorsement of the Moderna vaccine, for which the agency appears likely to soon also grant an EUA.

Marion Gruber, PhD, director of the Office of Vaccines Research and Review at FDA’s Center for Biologics Evaluation and Research, earlier rebuffed attempts by some of the panelists to alter the voting question. Some panelists wanted to make tweaks, including a rephrasing to underscore the limited nature of an EUA, compared with a more complete approval through the biologics license application (BLA) process.

FDA panelist Michael Kurilla, MD, PhD, of the National Institutes of Health was the only panelist to abstain from voting. He said he was uncomfortable with the phrasing of the question.

“In the midst of a pandemic and with limited vaccine supply available, a blanket statement for individuals 18 years and older is just too broad,” he said. “I’m not convinced that for all of those age groups the benefits do actually outweigh the risks.”

In general, though, there was strong support for Moderna’s vaccine. FDA panelist James Hildreth Sr, MD, PhD, of Meharry Medical College in Nashville, Tennessee spoke of the “remarkable achievement” seen in having two vaccines ready for clearance by December for a virus that only emerged as a threat this year.

Study data indicate the primary efficacy endpoint demonstrated vaccine efficacy (VE) of 94.1% (95% CI, 89.3% - 96.8%) for the Moderna vaccine, with 11 COVID-19 cases in the vaccine group and 185 COVID-19 cases in the placebo group, the FDA staff noted during the meeting.

The advisers and FDA staff also honed in on several key issues with COVID-19 vaccines, including the challenge of having people in the placebo groups of studies seek to get cleared vaccines. Also of concern to the panel were early reports of allergic reactions seen with the Pfizer product.

Doran L. Fink, MD, PhD, an FDA official who has been closely involved with the COVID-19 vaccines, told the panel that two healthcare workers in Alaska had allergic reactions minutes after receiving the Pfizer vaccine, one of which was a case of anaphylactic reaction that resulted in hospitalization.

In the United Kingdom, there were two cases reported of notable allergic reactions, leading regulators there to issue a warning that people who have a history of significant allergic reactions should not currently receive the Pfizer-BioNTech vaccine.

The people involved in these incidents have recovered or are recovering, Fink said. But the FDA expects there will be additional reports of allergic reactions to COVID-19 vaccines.

“These cases underscores the need to remain vigilant during the early phase of the vaccination campaign,” Fink said. “To this end, FDA is working with Pfizer to further revise factsheets and prescribing information for their vaccine to draw attention to CDC guidelines for post- vaccination monitoring and management of immediate allergic reactions.”

mRNA vaccines in the lead

An FDA emergency clearance for Moderna’s product would be another vote of confidence in a new approach to making vaccines. Both the Pfizer-BioNTech and Moderna vaccines provide the immune system with a kind of blueprint in the form of genetic material, mRNA. The mRNA sets the stage for the synthesis of the signature spike protein that the SARS-CoV-2 virus uses to attach to and infect human cells.

In a December 15 commentary for this news organization Michael E. Pichichero, MD, wrote that the “revolutionary aspect of mRNA vaccines is the speed at which they can be designed and produced.”

“This is why they lead the pack among the SARS-CoV-2 vaccine candidates and why the National Institute of Allergy and Infectious Diseases provided financial, technical, and/or clinical support. Indeed, once the amino acid sequence of a protein can be determined (a relatively easy task these days) it’s straightforward to synthesize mRNA in the lab — and it can be done incredibly fast,” he wrote.

The FDA allowed one waiver for panelist James K. Hildreth in connection with his personal relationship to a trial participant and his university’s participation in vaccine testing.

This article first appeared on Medscape.com.

Federal advisers on December 17 overwhelmingly recommended an emergency clearance to Moderna Inc’s COVID-19 vaccine, while noting concerns about potential allergic reactions and the challenges of continuing testing of this medicine.

The US Food and Drug Administration (FDA) put Moderna’s application before its Vaccines and Related Biological Products Advisory Committee. The panel voted 20-0 on this question: “Based on the totality of scientific evidence available, do the benefits of the Moderna COVID-19 Vaccine outweigh its risks for use in individuals 18 years of age and older?” There was one abstention.

The FDA is not bound to act on the recommendations of its advisers, but the agency usually takes the panel’s advice. The FDA cleared the similar Pfizer-BioNTech vaccine on December 11 through an emergency use authorization (EUA), following a positive vote for the product at a December 10 advisory committee meeting. In this case, the FDA staff appeared to be pushing for a broad endorsement of the Moderna vaccine, for which the agency appears likely to soon also grant an EUA.

Marion Gruber, PhD, director of the Office of Vaccines Research and Review at FDA’s Center for Biologics Evaluation and Research, earlier rebuffed attempts by some of the panelists to alter the voting question. Some panelists wanted to make tweaks, including a rephrasing to underscore the limited nature of an EUA, compared with a more complete approval through the biologics license application (BLA) process.

FDA panelist Michael Kurilla, MD, PhD, of the National Institutes of Health was the only panelist to abstain from voting. He said he was uncomfortable with the phrasing of the question.

“In the midst of a pandemic and with limited vaccine supply available, a blanket statement for individuals 18 years and older is just too broad,” he said. “I’m not convinced that for all of those age groups the benefits do actually outweigh the risks.”

In general, though, there was strong support for Moderna’s vaccine. FDA panelist James Hildreth Sr, MD, PhD, of Meharry Medical College in Nashville, Tennessee spoke of the “remarkable achievement” seen in having two vaccines ready for clearance by December for a virus that only emerged as a threat this year.

Study data indicate the primary efficacy endpoint demonstrated vaccine efficacy (VE) of 94.1% (95% CI, 89.3% - 96.8%) for the Moderna vaccine, with 11 COVID-19 cases in the vaccine group and 185 COVID-19 cases in the placebo group, the FDA staff noted during the meeting.

The advisers and FDA staff also honed in on several key issues with COVID-19 vaccines, including the challenge of having people in the placebo groups of studies seek to get cleared vaccines. Also of concern to the panel were early reports of allergic reactions seen with the Pfizer product.

Doran L. Fink, MD, PhD, an FDA official who has been closely involved with the COVID-19 vaccines, told the panel that two healthcare workers in Alaska had allergic reactions minutes after receiving the Pfizer vaccine, one of which was a case of anaphylactic reaction that resulted in hospitalization.

In the United Kingdom, there were two cases reported of notable allergic reactions, leading regulators there to issue a warning that people who have a history of significant allergic reactions should not currently receive the Pfizer-BioNTech vaccine.

The people involved in these incidents have recovered or are recovering, Fink said. But the FDA expects there will be additional reports of allergic reactions to COVID-19 vaccines.

“These cases underscores the need to remain vigilant during the early phase of the vaccination campaign,” Fink said. “To this end, FDA is working with Pfizer to further revise factsheets and prescribing information for their vaccine to draw attention to CDC guidelines for post- vaccination monitoring and management of immediate allergic reactions.”

mRNA vaccines in the lead

An FDA emergency clearance for Moderna’s product would be another vote of confidence in a new approach to making vaccines. Both the Pfizer-BioNTech and Moderna vaccines provide the immune system with a kind of blueprint in the form of genetic material, mRNA. The mRNA sets the stage for the synthesis of the signature spike protein that the SARS-CoV-2 virus uses to attach to and infect human cells.

In a December 15 commentary for this news organization Michael E. Pichichero, MD, wrote that the “revolutionary aspect of mRNA vaccines is the speed at which they can be designed and produced.”

“This is why they lead the pack among the SARS-CoV-2 vaccine candidates and why the National Institute of Allergy and Infectious Diseases provided financial, technical, and/or clinical support. Indeed, once the amino acid sequence of a protein can be determined (a relatively easy task these days) it’s straightforward to synthesize mRNA in the lab — and it can be done incredibly fast,” he wrote.

The FDA allowed one waiver for panelist James K. Hildreth in connection with his personal relationship to a trial participant and his university’s participation in vaccine testing.

This article first appeared on Medscape.com.

Bariatric surgery rates continue to climb in the setting of increasing obesity throughout the world. While effective at promoting weight loss, a growing body of literature has clearly demonstrated that bone loss and increased fracture risk occurs following bariatric surgery. However, major important questions remain regarding the impact of specific types of bariatric surgery on bone metabolism. Notably, most previous studies were not performed in a randomized manner with respect to the type of weight loss surgery. As such, indication bias exists with respect to current knowledge regarding how specific weight loss surgeries impact bone. Here, a randomized, triple-blind single center study in Norway assessed skeletal endpoints in patients with severe obesity and type 2 diabetes who were randomized to receive either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy weight loss surgery. The primary focus of this study, reported elsewhere, was to assess rates of diabetes remission. Areal bone mineral density in the hip and spine decreased significantly more one year after RYGB than after sleeve gastrectomy. The authors investigated serum bone turnover markers over time in these subjects. Both forms of bariatric surgery led to increases in bone formation and resorption markers, with higher levels of both markers seen after RYGB than sleeve gastrectomy. Importantly, these effects were independently associated with surgical procedure and not resultant weight change. Findings here strongly support the emerging notion that RYGB in particular is linked to high bone turnover and bone loss. While many hypotheses exist as to the underlying mechanism linking RYBG and bone loss, this remains an active and open area of investigation.

Denosumab, a neutralizing antibody against RANKL, is a potent antiresorptive agent that increases bone density and reduces fracture risk. In addition to its major role in osteoclast development, the paracrine-acting cytokine RANKL plays an important role in development and maintenance of the adaptive immune system. As such, a concern has been raised that denosumab treatment may increase risk of malignancies kept at bay by lymphoid surveillance. In this systematic review and meta-analysis of randomized controlled trials, the authors assessed risk of malignancy of denosumab versus comparator in 25 prospective randomized controlled trials. In these trials, >21,000 patients were analyzed who were treated for osteoporosis with either denosumab or control. The risk of malignancy was similar between osteoporosis denosumab dosing (60 mg every 6 months) and control. Drug exposure in these studies was up to 48 months. As such, additional post-marketing surveillance safety data are needed to address longer-term risks of malignancy. Nonetheless, these data are largely reassuring and provide additional evidence of the safety of denosumab therapy for osteoporosis.

Marc Wein, M.D., Ph.D
Assistant Professor of Medicine
Massachusetts General Hospital Endocrine Unit, Harvard Medical School

Bariatric surgery rates continue to climb in the setting of increasing obesity throughout the world. While effective at promoting weight loss, a growing body of literature has clearly demonstrated that bone loss and increased fracture risk occurs following bariatric surgery. However, major important questions remain regarding the impact of specific types of bariatric surgery on bone metabolism. Notably, most previous studies were not performed in a randomized manner with respect to the type of weight loss surgery. As such, indication bias exists with respect to current knowledge regarding how specific weight loss surgeries impact bone. Here, a randomized, triple-blind single center study in Norway assessed skeletal endpoints in patients with severe obesity and type 2 diabetes who were randomized to receive either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy weight loss surgery. The primary focus of this study, reported elsewhere, was to assess rates of diabetes remission. Areal bone mineral density in the hip and spine decreased significantly more one year after RYGB than after sleeve gastrectomy. The authors investigated serum bone turnover markers over time in these subjects. Both forms of bariatric surgery led to increases in bone formation and resorption markers, with higher levels of both markers seen after RYGB than sleeve gastrectomy. Importantly, these effects were independently associated with surgical procedure and not resultant weight change. Findings here strongly support the emerging notion that RYGB in particular is linked to high bone turnover and bone loss. While many hypotheses exist as to the underlying mechanism linking RYBG and bone loss, this remains an active and open area of investigation.

Denosumab, a neutralizing antibody against RANKL, is a potent antiresorptive agent that increases bone density and reduces fracture risk. In addition to its major role in osteoclast development, the paracrine-acting cytokine RANKL plays an important role in development and maintenance of the adaptive immune system. As such, a concern has been raised that denosumab treatment may increase risk of malignancies kept at bay by lymphoid surveillance. In this systematic review and meta-analysis of randomized controlled trials, the authors assessed risk of malignancy of denosumab versus comparator in 25 prospective randomized controlled trials. In these trials, >21,000 patients were analyzed who were treated for osteoporosis with either denosumab or control. The risk of malignancy was similar between osteoporosis denosumab dosing (60 mg every 6 months) and control. Drug exposure in these studies was up to 48 months. As such, additional post-marketing surveillance safety data are needed to address longer-term risks of malignancy. Nonetheless, these data are largely reassuring and provide additional evidence of the safety of denosumab therapy for osteoporosis.

Marc Wein, M.D., Ph.D
Assistant Professor of Medicine
Massachusetts General Hospital Endocrine Unit, Harvard Medical School

Bariatric surgery rates continue to climb in the setting of increasing obesity throughout the world. While effective at promoting weight loss, a growing body of literature has clearly demonstrated that bone loss and increased fracture risk occurs following bariatric surgery. However, major important questions remain regarding the impact of specific types of bariatric surgery on bone metabolism. Notably, most previous studies were not performed in a randomized manner with respect to the type of weight loss surgery. As such, indication bias exists with respect to current knowledge regarding how specific weight loss surgeries impact bone. Here, a randomized, triple-blind single center study in Norway assessed skeletal endpoints in patients with severe obesity and type 2 diabetes who were randomized to receive either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy weight loss surgery. The primary focus of this study, reported elsewhere, was to assess rates of diabetes remission. Areal bone mineral density in the hip and spine decreased significantly more one year after RYGB than after sleeve gastrectomy. The authors investigated serum bone turnover markers over time in these subjects. Both forms of bariatric surgery led to increases in bone formation and resorption markers, with higher levels of both markers seen after RYGB than sleeve gastrectomy. Importantly, these effects were independently associated with surgical procedure and not resultant weight change. Findings here strongly support the emerging notion that RYGB in particular is linked to high bone turnover and bone loss. While many hypotheses exist as to the underlying mechanism linking RYBG and bone loss, this remains an active and open area of investigation.

Denosumab, a neutralizing antibody against RANKL, is a potent antiresorptive agent that increases bone density and reduces fracture risk. In addition to its major role in osteoclast development, the paracrine-acting cytokine RANKL plays an important role in development and maintenance of the adaptive immune system. As such, a concern has been raised that denosumab treatment may increase risk of malignancies kept at bay by lymphoid surveillance. In this systematic review and meta-analysis of randomized controlled trials, the authors assessed risk of malignancy of denosumab versus comparator in 25 prospective randomized controlled trials. In these trials, >21,000 patients were analyzed who were treated for osteoporosis with either denosumab or control. The risk of malignancy was similar between osteoporosis denosumab dosing (60 mg every 6 months) and control. Drug exposure in these studies was up to 48 months. As such, additional post-marketing surveillance safety data are needed to address longer-term risks of malignancy. Nonetheless, these data are largely reassuring and provide additional evidence of the safety of denosumab therapy for osteoporosis.

Marc Wein, M.D., Ph.D
Assistant Professor of Medicine
Massachusetts General Hospital Endocrine Unit, Harvard Medical School

Key clinical point: Use of loop diuretics and nonuse of direct oral anticoagulants (DOACs) were independently associated with an increased risk of osteoporosis in patients with chronic heart failure (CHF).

Major finding: Use of loop diuretics (odds ratio [OR], 2.70; P less than .01) and nonuse of DOACs (OR for DOAC use, 0.36; P = .01) were associated with an increased risk for osteoporosis. Patients with osteoporotic BMD at 2 or 3 sites had a significantly higher rate of a composite of death and heart failure hospitalization than patients without osteoporosis (hazard ratio, 3.45; P less than .01).

Study details: The data come from a single-center, retrospective study of 303 (osteoporosis: n = 122; nonosteoporosis: n = 181) patients diagnosed with CHF.

Disclosures: The study was supported by a Grant-in-Aid for Young Scientists (S Katano) from the Japan Society for the Promotion of Science, KAKENHI, Tokyo, Japan. The authors reported no conflicts of interest. Dr. T Miura is a member of the Circulation Journal’s editorial team.

Source: Katano S et al. Circ J. 2020 Oct 28. doi: 10.1253/circj.CJ-20-0593.

Key clinical point: Use of loop diuretics and nonuse of direct oral anticoagulants (DOACs) were independently associated with an increased risk of osteoporosis in patients with chronic heart failure (CHF).

Major finding: Use of loop diuretics (odds ratio [OR], 2.70; P less than .01) and nonuse of DOACs (OR for DOAC use, 0.36; P = .01) were associated with an increased risk for osteoporosis. Patients with osteoporotic BMD at 2 or 3 sites had a significantly higher rate of a composite of death and heart failure hospitalization than patients without osteoporosis (hazard ratio, 3.45; P less than .01).

Study details: The data come from a single-center, retrospective study of 303 (osteoporosis: n = 122; nonosteoporosis: n = 181) patients diagnosed with CHF.

Disclosures: The study was supported by a Grant-in-Aid for Young Scientists (S Katano) from the Japan Society for the Promotion of Science, KAKENHI, Tokyo, Japan. The authors reported no conflicts of interest. Dr. T Miura is a member of the Circulation Journal’s editorial team.

Source: Katano S et al. Circ J. 2020 Oct 28. doi: 10.1253/circj.CJ-20-0593.

Key clinical point: Use of loop diuretics and nonuse of direct oral anticoagulants (DOACs) were independently associated with an increased risk of osteoporosis in patients with chronic heart failure (CHF).

Major finding: Use of loop diuretics (odds ratio [OR], 2.70; P less than .01) and nonuse of DOACs (OR for DOAC use, 0.36; P = .01) were associated with an increased risk for osteoporosis. Patients with osteoporotic BMD at 2 or 3 sites had a significantly higher rate of a composite of death and heart failure hospitalization than patients without osteoporosis (hazard ratio, 3.45; P less than .01).

Study details: The data come from a single-center, retrospective study of 303 (osteoporosis: n = 122; nonosteoporosis: n = 181) patients diagnosed with CHF.

Disclosures: The study was supported by a Grant-in-Aid for Young Scientists (S Katano) from the Japan Society for the Promotion of Science, KAKENHI, Tokyo, Japan. The authors reported no conflicts of interest. Dr. T Miura is a member of the Circulation Journal’s editorial team.

Source: Katano S et al. Circ J. 2020 Oct 28. doi: 10.1253/circj.CJ-20-0593.

Key clinical point: Switching to denosumab (Dmab) from bisphosphonates (BP) or selective estrogen receptor modulator (SERM) significantly suppressed osteoporosis progression in postmenopausal women with type 2 diabetes (T2D).

Major finding: SERM-Dmab vs. SERM-SERM group showed significantly higher percentage change (P less than .04) in lumbar spine bone mineral density. BP-Dmab and SERM-Dmab groups showed a significantly lower percentage change in serum bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b compared with the BP-BP and SERM-SERM groups, respectively (P less than .05 for all).

Study details: The data come from a 24-week, prospective, parallel-group, observational study of 48 T2D postmenopausal patients with osteoporosis who were either switched from BP or SERM to Dmab (BP-Dmab group/SERM-Dmab group, respectively) or continued BP or SERM therapy (BP-BP group/SERM-SERM group, respectively).

Disclosures: The study received no financial support. A Nakamura, T Astumi, and H Miyoshi received honoraria for lectures and research funding from various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Miyoshi A et al. J Diabetes Investig. 2020 Nov 3. doi: 10.1111/jdi.13458.

Key clinical point: Switching to denosumab (Dmab) from bisphosphonates (BP) or selective estrogen receptor modulator (SERM) significantly suppressed osteoporosis progression in postmenopausal women with type 2 diabetes (T2D).

Major finding: SERM-Dmab vs. SERM-SERM group showed significantly higher percentage change (P less than .04) in lumbar spine bone mineral density. BP-Dmab and SERM-Dmab groups showed a significantly lower percentage change in serum bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b compared with the BP-BP and SERM-SERM groups, respectively (P less than .05 for all).

Study details: The data come from a 24-week, prospective, parallel-group, observational study of 48 T2D postmenopausal patients with osteoporosis who were either switched from BP or SERM to Dmab (BP-Dmab group/SERM-Dmab group, respectively) or continued BP or SERM therapy (BP-BP group/SERM-SERM group, respectively).

Disclosures: The study received no financial support. A Nakamura, T Astumi, and H Miyoshi received honoraria for lectures and research funding from various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Miyoshi A et al. J Diabetes Investig. 2020 Nov 3. doi: 10.1111/jdi.13458.

Key clinical point: Switching to denosumab (Dmab) from bisphosphonates (BP) or selective estrogen receptor modulator (SERM) significantly suppressed osteoporosis progression in postmenopausal women with type 2 diabetes (T2D).

Major finding: SERM-Dmab vs. SERM-SERM group showed significantly higher percentage change (P less than .04) in lumbar spine bone mineral density. BP-Dmab and SERM-Dmab groups showed a significantly lower percentage change in serum bone-specific alkaline phosphatase and tartrate-resistant acid phosphatase 5b compared with the BP-BP and SERM-SERM groups, respectively (P less than .05 for all).

Study details: The data come from a 24-week, prospective, parallel-group, observational study of 48 T2D postmenopausal patients with osteoporosis who were either switched from BP or SERM to Dmab (BP-Dmab group/SERM-Dmab group, respectively) or continued BP or SERM therapy (BP-BP group/SERM-SERM group, respectively).

Disclosures: The study received no financial support. A Nakamura, T Astumi, and H Miyoshi received honoraria for lectures and research funding from various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Miyoshi A et al. J Diabetes Investig. 2020 Nov 3. doi: 10.1111/jdi.13458.

Key clinical point: The prevalence of periapical lesions is significantly higher in patients with vs. without osteoporosis. Patients treated with bisphosphonates (BPs) have a lower prevalence of periapical lesions.

Major finding: The prevalence of periapical lesions in patients with osteoporosis was significantly higher compared with the general patient population in the hospital (odds ratio, 3.36; P less than .0001). Treatment with BPs was associated with a lower prevalence of periapical lesions than no treatment with BPs (P less than.0001).

Study details: Analysis of data from 1,644,953 individuals, including admitted patients as well as outpatients.

Disclosures: No study sponsor was identified. The authors declared no conflicts of interest.

Source: Katz J et al. J Endod. 2020 Oct 28. doi: 10.1016/j.joen.2020.10.019.

Key clinical point: The prevalence of periapical lesions is significantly higher in patients with vs. without osteoporosis. Patients treated with bisphosphonates (BPs) have a lower prevalence of periapical lesions.

Major finding: The prevalence of periapical lesions in patients with osteoporosis was significantly higher compared with the general patient population in the hospital (odds ratio, 3.36; P less than .0001). Treatment with BPs was associated with a lower prevalence of periapical lesions than no treatment with BPs (P less than.0001).

Study details: Analysis of data from 1,644,953 individuals, including admitted patients as well as outpatients.

Disclosures: No study sponsor was identified. The authors declared no conflicts of interest.

Source: Katz J et al. J Endod. 2020 Oct 28. doi: 10.1016/j.joen.2020.10.019.

Key clinical point: The prevalence of periapical lesions is significantly higher in patients with vs. without osteoporosis. Patients treated with bisphosphonates (BPs) have a lower prevalence of periapical lesions.

Major finding: The prevalence of periapical lesions in patients with osteoporosis was significantly higher compared with the general patient population in the hospital (odds ratio, 3.36; P less than .0001). Treatment with BPs was associated with a lower prevalence of periapical lesions than no treatment with BPs (P less than.0001).

Study details: Analysis of data from 1,644,953 individuals, including admitted patients as well as outpatients.

Disclosures: No study sponsor was identified. The authors declared no conflicts of interest.

Source: Katz J et al. J Endod. 2020 Oct 28. doi: 10.1016/j.joen.2020.10.019.

Key clinical point: Patients with impaired fasting glucose (IFG) and diabetes mellitus (DM) have a lower risk for incident osteoporosis.

Major finding: The risk of osteoporosis significantly decreased (P less than .001 for all) above the fourth quartile of fasting glucose levels in men and above the third quartile in women compared with the first quartile. The risk of osteoporosis was significantly lower (P less than .001 for all) with IFG (men: hazard ratio [HR], 0.84; women: HR, 0.93) and DM (men: HR, 0.77; women: HR, 0.75) compared with the normal glucose group.

Study details: The data come from a retrospective study of 96,626 patients.

Disclosures: No study sponsor was identified. The authors declared no conflicts of interest.

Source: Park SK et al. Bone. 2020 Oct 21. doi: 10.1016/j.bone.2020.115690.

Key clinical point: Patients with impaired fasting glucose (IFG) and diabetes mellitus (DM) have a lower risk for incident osteoporosis.

Major finding: The risk of osteoporosis significantly decreased (P less than .001 for all) above the fourth quartile of fasting glucose levels in men and above the third quartile in women compared with the first quartile. The risk of osteoporosis was significantly lower (P less than .001 for all) with IFG (men: hazard ratio [HR], 0.84; women: HR, 0.93) and DM (men: HR, 0.77; women: HR, 0.75) compared with the normal glucose group.

Study details: The data come from a retrospective study of 96,626 patients.

Disclosures: No study sponsor was identified. The authors declared no conflicts of interest.

Source: Park SK et al. Bone. 2020 Oct 21. doi: 10.1016/j.bone.2020.115690.

Key clinical point: Patients with impaired fasting glucose (IFG) and diabetes mellitus (DM) have a lower risk for incident osteoporosis.

Major finding: The risk of osteoporosis significantly decreased (P less than .001 for all) above the fourth quartile of fasting glucose levels in men and above the third quartile in women compared with the first quartile. The risk of osteoporosis was significantly lower (P less than .001 for all) with IFG (men: hazard ratio [HR], 0.84; women: HR, 0.93) and DM (men: HR, 0.77; women: HR, 0.75) compared with the normal glucose group.

Study details: The data come from a retrospective study of 96,626 patients.

Disclosures: No study sponsor was identified. The authors declared no conflicts of interest.

Source: Park SK et al. Bone. 2020 Oct 21. doi: 10.1016/j.bone.2020.115690.

Key clinical point: Psoriasis was associated with an elevated risk of osteoporosis in individuals aged 40 years or older.

Major finding: In study 1 (a follow-up study), the psoriasis group had a significantly higher risk of osteoporosis than the control group (adjusted hazard ratio, 1.09; P less than .001). In study 2 (a nested case-control study), the osteoporosis group had a significantly higher prevalence of psoriasis than the control group (adjusted odds ratio, 1.21; P less than .001).

Study details: A total of 25,306 patients with psoriasis were matched (1:4) to 101,224 controls (study 1) and 79,212 patients with osteoporosis were matched (1:1) to 79,212 controls (study 2).

Disclosures: The work was supported in part by a research grant from the National Research Foundation of Korea. The authors reported no conflicts of interest.

Source: Lee JW et al. Osteoporos Int. 2020 Nov 5. doi: 10.1007/s00198-020-05724-2.

Key clinical point: Psoriasis was associated with an elevated risk of osteoporosis in individuals aged 40 years or older.

Major finding: In study 1 (a follow-up study), the psoriasis group had a significantly higher risk of osteoporosis than the control group (adjusted hazard ratio, 1.09; P less than .001). In study 2 (a nested case-control study), the osteoporosis group had a significantly higher prevalence of psoriasis than the control group (adjusted odds ratio, 1.21; P less than .001).

Study details: A total of 25,306 patients with psoriasis were matched (1:4) to 101,224 controls (study 1) and 79,212 patients with osteoporosis were matched (1:1) to 79,212 controls (study 2).

Disclosures: The work was supported in part by a research grant from the National Research Foundation of Korea. The authors reported no conflicts of interest.

Source: Lee JW et al. Osteoporos Int. 2020 Nov 5. doi: 10.1007/s00198-020-05724-2.

Key clinical point: Psoriasis was associated with an elevated risk of osteoporosis in individuals aged 40 years or older.

Major finding: In study 1 (a follow-up study), the psoriasis group had a significantly higher risk of osteoporosis than the control group (adjusted hazard ratio, 1.09; P less than .001). In study 2 (a nested case-control study), the osteoporosis group had a significantly higher prevalence of psoriasis than the control group (adjusted odds ratio, 1.21; P less than .001).

Study details: A total of 25,306 patients with psoriasis were matched (1:4) to 101,224 controls (study 1) and 79,212 patients with osteoporosis were matched (1:1) to 79,212 controls (study 2).

Disclosures: The work was supported in part by a research grant from the National Research Foundation of Korea. The authors reported no conflicts of interest.

Source: Lee JW et al. Osteoporos Int. 2020 Nov 5. doi: 10.1007/s00198-020-05724-2.

Key clinical point: Romosozumab followed by denosumab results in significant bone mineral density (BMD) gains and numerically lower vertebral fractures in postmenopausal Japanese women with osteoporosis at high risk of fracture vs. placebo followed by denosumab through 36 months of follow-up.

Major finding: At 12, 24, and 36 months, the incidence of new vertebral fractures was lower with romosozumab/denosumab vs. placebo/denosumab (relative risk reduction at all timepoints: 84%; P = .056). BMD increase at 12, 24, and 36 months were greater with romosozumab/denosumab vs. placebo/denosumab (lumbar spine: 16.3%, 21.5%, and 23.2% vs. 0.4%, 8.1%, and 10.4%; total hip: 4.9%, 7.9%, and 8.9% vs. 0.4%, 2.8%, and 4.1%; femoral neck: 4.8%, 7.6%, and 8.1% vs. 0.3%, 3.3%, and 3.7%, respectively; all P less than .001).

Study details: This post hoc analysis of phase 3 FRAME study included 187 postmenopausal Japanese women with osteoporosis at high risk of fracture (romosozumab/denosumab group, n = 91; placebo/denosumab group, n = 96).

Disclosures: This study was funded by Amgen Inc., Astellas, and UCB Pharma. A Miyauchi received consulting fees from Amgen, Astellas BioPharma K.K., and Teijin Pharma. E Hamaya, K Nishi, and J Shimauchi are employees of Amgen K.K., Japan, and E Hamaya holds stock in Amgen Inc. W Yang is an employee of Amgen Inc., USA. C Libanati is an employee of UCB Pharma, Belgium, and holds stock in UCB Pharma. C Tolman is an employee of Amgen and holds stock in Amgen.

Source: Miyauchi A et al. J Bone Miner Metab. 2020 Oct 15. doi: 10.1007/s00774-020-01147-5.

Key clinical point: Romosozumab followed by denosumab results in significant bone mineral density (BMD) gains and numerically lower vertebral fractures in postmenopausal Japanese women with osteoporosis at high risk of fracture vs. placebo followed by denosumab through 36 months of follow-up.

Major finding: At 12, 24, and 36 months, the incidence of new vertebral fractures was lower with romosozumab/denosumab vs. placebo/denosumab (relative risk reduction at all timepoints: 84%; P = .056). BMD increase at 12, 24, and 36 months were greater with romosozumab/denosumab vs. placebo/denosumab (lumbar spine: 16.3%, 21.5%, and 23.2% vs. 0.4%, 8.1%, and 10.4%; total hip: 4.9%, 7.9%, and 8.9% vs. 0.4%, 2.8%, and 4.1%; femoral neck: 4.8%, 7.6%, and 8.1% vs. 0.3%, 3.3%, and 3.7%, respectively; all P less than .001).

Study details: This post hoc analysis of phase 3 FRAME study included 187 postmenopausal Japanese women with osteoporosis at high risk of fracture (romosozumab/denosumab group, n = 91; placebo/denosumab group, n = 96).

Disclosures: This study was funded by Amgen Inc., Astellas, and UCB Pharma. A Miyauchi received consulting fees from Amgen, Astellas BioPharma K.K., and Teijin Pharma. E Hamaya, K Nishi, and J Shimauchi are employees of Amgen K.K., Japan, and E Hamaya holds stock in Amgen Inc. W Yang is an employee of Amgen Inc., USA. C Libanati is an employee of UCB Pharma, Belgium, and holds stock in UCB Pharma. C Tolman is an employee of Amgen and holds stock in Amgen.

Source: Miyauchi A et al. J Bone Miner Metab. 2020 Oct 15. doi: 10.1007/s00774-020-01147-5.

Key clinical point: Romosozumab followed by denosumab results in significant bone mineral density (BMD) gains and numerically lower vertebral fractures in postmenopausal Japanese women with osteoporosis at high risk of fracture vs. placebo followed by denosumab through 36 months of follow-up.

Major finding: At 12, 24, and 36 months, the incidence of new vertebral fractures was lower with romosozumab/denosumab vs. placebo/denosumab (relative risk reduction at all timepoints: 84%; P = .056). BMD increase at 12, 24, and 36 months were greater with romosozumab/denosumab vs. placebo/denosumab (lumbar spine: 16.3%, 21.5%, and 23.2% vs. 0.4%, 8.1%, and 10.4%; total hip: 4.9%, 7.9%, and 8.9% vs. 0.4%, 2.8%, and 4.1%; femoral neck: 4.8%, 7.6%, and 8.1% vs. 0.3%, 3.3%, and 3.7%, respectively; all P less than .001).

Study details: This post hoc analysis of phase 3 FRAME study included 187 postmenopausal Japanese women with osteoporosis at high risk of fracture (romosozumab/denosumab group, n = 91; placebo/denosumab group, n = 96).

Disclosures: This study was funded by Amgen Inc., Astellas, and UCB Pharma. A Miyauchi received consulting fees from Amgen, Astellas BioPharma K.K., and Teijin Pharma. E Hamaya, K Nishi, and J Shimauchi are employees of Amgen K.K., Japan, and E Hamaya holds stock in Amgen Inc. W Yang is an employee of Amgen Inc., USA. C Libanati is an employee of UCB Pharma, Belgium, and holds stock in UCB Pharma. C Tolman is an employee of Amgen and holds stock in Amgen.

Source: Miyauchi A et al. J Bone Miner Metab. 2020 Oct 15. doi: 10.1007/s00774-020-01147-5.