Menopause

Vinogradova Y, Dening T, Hippisley-Cox J, et al. Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases. BMJ. 2021;374:n2182. doi: 10.1136/bmj.n2182.

Much interest has surrounded whether the use of menopausal HT impacts future risk of cognitive decline. Recently, Vinogradova and colleagues conducted an observational study using data from 2 large primary care databases, QResearch and the Clinical Practice Research Datalink (CPRD), in the United Kingdom.¹ The investigators conducted case-control studies that included women aged 55 and older diagnosed with dementia and up to 5 controls without dementia. Only cases and controls with at least 10 years of medical records prior to the index date (that is, the time of dementia diagnosis in cases) were included. Since early symptoms of dementia prior to diagnosis may cause sleep problems and dysphoria (which also may be symptoms of menopause), HT prescriptions during the 3 years prior to the index date were excluded.

Details of the study

Among 16,291 cases and 68,726 controls, the women’s mean age was approximately 83 years. Cases were identified by using codes for dementia from patients’ clinical records or records of prescriptions for drugs used to treat dementia.

More than half the women were being treated for hypertension, and 14% of women in both groups had used HT. Women were considered users of estrogen-only therapy if they had no prescriptions containing a progestogen after their first prescription for systemic estrogen as the start of exposure to HT. Those with any subsequent prescription containing a progestogen were classified as combined HT users.

Results. In an analysis adjusted for all available potential confounders—including lifestyle factors, ethnicity, family history of dementia, early menopause, oophorectomy/ hysterectomy, comorbidities, and use of other relevant drugs—the use of HT was not associated with risk of dementia.

A reduced risk of dementia was noted among women who had been taking estrogen-only HT for 10 years or more (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.76–0.94). An elevated risk of Alzheimer disease was noted among women who had used estrogen-progestin HT for 5 to 9 years (OR, 1.19; CI, 1.06–1.33).¹

Study strengths and limitations

The authors pointed out that this study’s main strengths were that it had a very large sample size representative of the general population and that its design permitted capture of all known cases as well as precision recording for prescribed drugs. On the other hand, the study is limited by the possible lack of data for some older women before the index date; that is, menopause in this latter group started before their registration or before these data were gathered electronically by their practice. ●

Vinogradova Y, Dening T, Hippisley-Cox J, et al. Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases. BMJ. 2021;374:n2182. doi: 10.1136/bmj.n2182.

Much interest has surrounded whether the use of menopausal HT impacts future risk of cognitive decline. Recently, Vinogradova and colleagues conducted an observational study using data from 2 large primary care databases, QResearch and the Clinical Practice Research Datalink (CPRD), in the United Kingdom.¹ The investigators conducted case-control studies that included women aged 55 and older diagnosed with dementia and up to 5 controls without dementia. Only cases and controls with at least 10 years of medical records prior to the index date (that is, the time of dementia diagnosis in cases) were included. Since early symptoms of dementia prior to diagnosis may cause sleep problems and dysphoria (which also may be symptoms of menopause), HT prescriptions during the 3 years prior to the index date were excluded.

Details of the study

Among 16,291 cases and 68,726 controls, the women’s mean age was approximately 83 years. Cases were identified by using codes for dementia from patients’ clinical records or records of prescriptions for drugs used to treat dementia.

More than half the women were being treated for hypertension, and 14% of women in both groups had used HT. Women were considered users of estrogen-only therapy if they had no prescriptions containing a progestogen after their first prescription for systemic estrogen as the start of exposure to HT. Those with any subsequent prescription containing a progestogen were classified as combined HT users.

Results. In an analysis adjusted for all available potential confounders—including lifestyle factors, ethnicity, family history of dementia, early menopause, oophorectomy/ hysterectomy, comorbidities, and use of other relevant drugs—the use of HT was not associated with risk of dementia.

A reduced risk of dementia was noted among women who had been taking estrogen-only HT for 10 years or more (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.76–0.94). An elevated risk of Alzheimer disease was noted among women who had used estrogen-progestin HT for 5 to 9 years (OR, 1.19; CI, 1.06–1.33).¹

Study strengths and limitations

The authors pointed out that this study’s main strengths were that it had a very large sample size representative of the general population and that its design permitted capture of all known cases as well as precision recording for prescribed drugs. On the other hand, the study is limited by the possible lack of data for some older women before the index date; that is, menopause in this latter group started before their registration or before these data were gathered electronically by their practice. ●

Vinogradova Y, Dening T, Hippisley-Cox J, et al. Use of menopausal hormone therapy and risk of dementia: nested case-control studies using QResearch and CPRD databases. BMJ. 2021;374:n2182. doi: 10.1136/bmj.n2182.

Much interest has surrounded whether the use of menopausal HT impacts future risk of cognitive decline. Recently, Vinogradova and colleagues conducted an observational study using data from 2 large primary care databases, QResearch and the Clinical Practice Research Datalink (CPRD), in the United Kingdom.¹ The investigators conducted case-control studies that included women aged 55 and older diagnosed with dementia and up to 5 controls without dementia. Only cases and controls with at least 10 years of medical records prior to the index date (that is, the time of dementia diagnosis in cases) were included. Since early symptoms of dementia prior to diagnosis may cause sleep problems and dysphoria (which also may be symptoms of menopause), HT prescriptions during the 3 years prior to the index date were excluded.

Details of the study

Among 16,291 cases and 68,726 controls, the women’s mean age was approximately 83 years. Cases were identified by using codes for dementia from patients’ clinical records or records of prescriptions for drugs used to treat dementia.

More than half the women were being treated for hypertension, and 14% of women in both groups had used HT. Women were considered users of estrogen-only therapy if they had no prescriptions containing a progestogen after their first prescription for systemic estrogen as the start of exposure to HT. Those with any subsequent prescription containing a progestogen were classified as combined HT users.

Results. In an analysis adjusted for all available potential confounders—including lifestyle factors, ethnicity, family history of dementia, early menopause, oophorectomy/ hysterectomy, comorbidities, and use of other relevant drugs—the use of HT was not associated with risk of dementia.

A reduced risk of dementia was noted among women who had been taking estrogen-only HT for 10 years or more (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.76–0.94). An elevated risk of Alzheimer disease was noted among women who had used estrogen-progestin HT for 5 to 9 years (OR, 1.19; CI, 1.06–1.33).¹

Study strengths and limitations

The authors pointed out that this study’s main strengths were that it had a very large sample size representative of the general population and that its design permitted capture of all known cases as well as precision recording for prescribed drugs. On the other hand, the study is limited by the possible lack of data for some older women before the index date; that is, menopause in this latter group started before their registration or before these data were gathered electronically by their practice. ●

Researchers found a small but greater risk of a hip fracture after 2 years of taking a “drug holiday” – stopping therapy – after long-term (≥3-year) use of one bisphosphonate, risedronate, versus another, alendronate.   

The risk of a hip fracture after stopping either of these oral bisphosphonate osteoporosis drugs was similar until 2 years, suggesting that patients who take a drug holiday from risedronate should be revaluated before 2 years.

These top-line findings from a propensity-matched cohort study of older patients in Ontario, Canada, were reported at the annual American Society of Bone and Mineral Research (ASBMR) last fall.

The full study, led by Kaleen N. Hayes, PharmD, PhD, Brown University School of Public Health, Providence, R.I., was published online in the Annals of Internal Medicine.

“We emphasize that our results do not indicate that alendronate therapy should be preferred over risedronate therapy,” the researchers stress, as several real-world studies found a similar risk of fractures while patients were receiving either drug.

“The decision to initiate alendronate or risedronate therapy [the two most commonly prescribed bisphosphonates] is driven by the prescriber,” they note, adding that some patients may prefer risedronate because it is available as a monthly dose or a weekly delayed-release formula that does not require fasting. 

“We found little difference in the association between risedronate versus alendronate drug holidays and hip fractures until approximately 2 years of not receiving therapy,” Dr. Hayes and colleagues summarize.

Over 3 years, risedronate drug holidays were associated with an 18% relative and 0.6% absolute increased risk for hip fracture compared with alendronate drug holidays.

“To further inform clinical decision-making on drug holidays,” they conclude, “future research should examine when to start and restart osteoporosis therapy on the basis of initial length and type of treatment, patient characteristics, and relative risk for hip fractures versus [atypical femoral fracture].”
 

Hip fracture risk with risedronate vs. alendronate drug holiday

Long-term bisphosphonate use is associated with a rare risk of osteonecrosis of the jaw or atypical femoral fractures. At the same time, bisphosphonates continue to have a therapeutic effect after therapy is discontinued.

Guidelines recommend that patients at low risk of fracture should therefore have a “drug holiday” after 3 to 5 years of bisphosphonate use and be reassessed 2 to 3 years later, largely based on the Fracture Intervention Trial Long-Term Extension (FLEX) study of alendronate. But risedronate has a shorter half-life, so it may provide shorter residual fracture protection.

Using Ontario administrative data, Dr. Hayes and associates identified more than 60,000 patients who were over aged 65, had received at least 3 years of continuous alendronate or risedronate, and had a subsequent 3-year drug holiday between 2000 and 2020.

They excluded patients who had a fracture or entered a nursing home within 120 days of starting a drug holiday who may have stopped the bisphosphonate due to declining health rather than a drug holiday.

Roughly half (55%) had been taking risedronate and 45% had been taking alendronate.

Using propensity scores, the researchers matched 25,077 patients who had been taking risedronate with an equal number who had been taking alendronate.

Most of the patients were women (82%) and were White.

They started the drug holiday when they were on average 81 years old, after taking the bisphosphonate for 5.9 years on average.

During the 3-year drug holiday, 915 of the 50,154 patients had hip fractures.

This was equivalent to 12.4 hip fractures per 1,000 patients per year during a risedronate holiday and 10.6 hip fractures per 1,000 patients per year during an alendronate holiday (hazard ratio, 1.18).  

The risk of hip fracture was not significantly higher at 1 year (HR, 1.03) or at 2 years of a risedronate holiday versus an alendronate holiday (HR, 1.14).

However, the risk of a hip fracture was significantly higher at 2 to 3 years of a risedronate holiday than after an alendronate holiday (HR, 1.34). 

There was no significant difference in the risk of any osteoporotic fracture overall (including hip, vertebrae, pelvis, ribs, forearm), however, during a 3-year risedronate versus alendronate drug holiday (HR, 1.07).

The research was supported by the Canadian Institutes of Health Research and Institute for Clinical Evaluative Sciences. Dr. Hayes was supported by a CIHR doctoral research award. The authors have reported no relevant financial relationships.

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

Researchers found a small but greater risk of a hip fracture after 2 years of taking a “drug holiday” – stopping therapy – after long-term (≥3-year) use of one bisphosphonate, risedronate, versus another, alendronate.   

The risk of a hip fracture after stopping either of these oral bisphosphonate osteoporosis drugs was similar until 2 years, suggesting that patients who take a drug holiday from risedronate should be revaluated before 2 years.

These top-line findings from a propensity-matched cohort study of older patients in Ontario, Canada, were reported at the annual American Society of Bone and Mineral Research (ASBMR) last fall.

The full study, led by Kaleen N. Hayes, PharmD, PhD, Brown University School of Public Health, Providence, R.I., was published online in the Annals of Internal Medicine.

“We emphasize that our results do not indicate that alendronate therapy should be preferred over risedronate therapy,” the researchers stress, as several real-world studies found a similar risk of fractures while patients were receiving either drug.

“The decision to initiate alendronate or risedronate therapy [the two most commonly prescribed bisphosphonates] is driven by the prescriber,” they note, adding that some patients may prefer risedronate because it is available as a monthly dose or a weekly delayed-release formula that does not require fasting. 

“We found little difference in the association between risedronate versus alendronate drug holidays and hip fractures until approximately 2 years of not receiving therapy,” Dr. Hayes and colleagues summarize.

Over 3 years, risedronate drug holidays were associated with an 18% relative and 0.6% absolute increased risk for hip fracture compared with alendronate drug holidays.

“To further inform clinical decision-making on drug holidays,” they conclude, “future research should examine when to start and restart osteoporosis therapy on the basis of initial length and type of treatment, patient characteristics, and relative risk for hip fractures versus [atypical femoral fracture].”
 

Hip fracture risk with risedronate vs. alendronate drug holiday

Long-term bisphosphonate use is associated with a rare risk of osteonecrosis of the jaw or atypical femoral fractures. At the same time, bisphosphonates continue to have a therapeutic effect after therapy is discontinued.

Guidelines recommend that patients at low risk of fracture should therefore have a “drug holiday” after 3 to 5 years of bisphosphonate use and be reassessed 2 to 3 years later, largely based on the Fracture Intervention Trial Long-Term Extension (FLEX) study of alendronate. But risedronate has a shorter half-life, so it may provide shorter residual fracture protection.

Using Ontario administrative data, Dr. Hayes and associates identified more than 60,000 patients who were over aged 65, had received at least 3 years of continuous alendronate or risedronate, and had a subsequent 3-year drug holiday between 2000 and 2020.

They excluded patients who had a fracture or entered a nursing home within 120 days of starting a drug holiday who may have stopped the bisphosphonate due to declining health rather than a drug holiday.

Roughly half (55%) had been taking risedronate and 45% had been taking alendronate.

Using propensity scores, the researchers matched 25,077 patients who had been taking risedronate with an equal number who had been taking alendronate.

Most of the patients were women (82%) and were White.

They started the drug holiday when they were on average 81 years old, after taking the bisphosphonate for 5.9 years on average.

During the 3-year drug holiday, 915 of the 50,154 patients had hip fractures.

This was equivalent to 12.4 hip fractures per 1,000 patients per year during a risedronate holiday and 10.6 hip fractures per 1,000 patients per year during an alendronate holiday (hazard ratio, 1.18).  

The risk of hip fracture was not significantly higher at 1 year (HR, 1.03) or at 2 years of a risedronate holiday versus an alendronate holiday (HR, 1.14).

However, the risk of a hip fracture was significantly higher at 2 to 3 years of a risedronate holiday than after an alendronate holiday (HR, 1.34). 

There was no significant difference in the risk of any osteoporotic fracture overall (including hip, vertebrae, pelvis, ribs, forearm), however, during a 3-year risedronate versus alendronate drug holiday (HR, 1.07).

The research was supported by the Canadian Institutes of Health Research and Institute for Clinical Evaluative Sciences. Dr. Hayes was supported by a CIHR doctoral research award. The authors have reported no relevant financial relationships.

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

Researchers found a small but greater risk of a hip fracture after 2 years of taking a “drug holiday” – stopping therapy – after long-term (≥3-year) use of one bisphosphonate, risedronate, versus another, alendronate.   

The risk of a hip fracture after stopping either of these oral bisphosphonate osteoporosis drugs was similar until 2 years, suggesting that patients who take a drug holiday from risedronate should be revaluated before 2 years.

These top-line findings from a propensity-matched cohort study of older patients in Ontario, Canada, were reported at the annual American Society of Bone and Mineral Research (ASBMR) last fall.

The full study, led by Kaleen N. Hayes, PharmD, PhD, Brown University School of Public Health, Providence, R.I., was published online in the Annals of Internal Medicine.

“We emphasize that our results do not indicate that alendronate therapy should be preferred over risedronate therapy,” the researchers stress, as several real-world studies found a similar risk of fractures while patients were receiving either drug.

“The decision to initiate alendronate or risedronate therapy [the two most commonly prescribed bisphosphonates] is driven by the prescriber,” they note, adding that some patients may prefer risedronate because it is available as a monthly dose or a weekly delayed-release formula that does not require fasting. 

“We found little difference in the association between risedronate versus alendronate drug holidays and hip fractures until approximately 2 years of not receiving therapy,” Dr. Hayes and colleagues summarize.

Over 3 years, risedronate drug holidays were associated with an 18% relative and 0.6% absolute increased risk for hip fracture compared with alendronate drug holidays.

“To further inform clinical decision-making on drug holidays,” they conclude, “future research should examine when to start and restart osteoporosis therapy on the basis of initial length and type of treatment, patient characteristics, and relative risk for hip fractures versus [atypical femoral fracture].”
 

Hip fracture risk with risedronate vs. alendronate drug holiday

Long-term bisphosphonate use is associated with a rare risk of osteonecrosis of the jaw or atypical femoral fractures. At the same time, bisphosphonates continue to have a therapeutic effect after therapy is discontinued.

Guidelines recommend that patients at low risk of fracture should therefore have a “drug holiday” after 3 to 5 years of bisphosphonate use and be reassessed 2 to 3 years later, largely based on the Fracture Intervention Trial Long-Term Extension (FLEX) study of alendronate. But risedronate has a shorter half-life, so it may provide shorter residual fracture protection.

Using Ontario administrative data, Dr. Hayes and associates identified more than 60,000 patients who were over aged 65, had received at least 3 years of continuous alendronate or risedronate, and had a subsequent 3-year drug holiday between 2000 and 2020.

They excluded patients who had a fracture or entered a nursing home within 120 days of starting a drug holiday who may have stopped the bisphosphonate due to declining health rather than a drug holiday.

Roughly half (55%) had been taking risedronate and 45% had been taking alendronate.

Using propensity scores, the researchers matched 25,077 patients who had been taking risedronate with an equal number who had been taking alendronate.

Most of the patients were women (82%) and were White.

They started the drug holiday when they were on average 81 years old, after taking the bisphosphonate for 5.9 years on average.

During the 3-year drug holiday, 915 of the 50,154 patients had hip fractures.

This was equivalent to 12.4 hip fractures per 1,000 patients per year during a risedronate holiday and 10.6 hip fractures per 1,000 patients per year during an alendronate holiday (hazard ratio, 1.18).  

The risk of hip fracture was not significantly higher at 1 year (HR, 1.03) or at 2 years of a risedronate holiday versus an alendronate holiday (HR, 1.14).

However, the risk of a hip fracture was significantly higher at 2 to 3 years of a risedronate holiday than after an alendronate holiday (HR, 1.34). 

There was no significant difference in the risk of any osteoporotic fracture overall (including hip, vertebrae, pelvis, ribs, forearm), however, during a 3-year risedronate versus alendronate drug holiday (HR, 1.07).

The research was supported by the Canadian Institutes of Health Research and Institute for Clinical Evaluative Sciences. Dr. Hayes was supported by a CIHR doctoral research award. The authors have reported no relevant financial relationships.

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

Even though men in midlife have more cardiovascular (CV) conditions and risk factors than women of the same age, women are more affected by these conditions in terms of cognitive decline, new research suggests.

Analyses of almost 1,400 participants in the population-based Mayo Clinic Study of Aging showed that diabetes, dyslipidemia, and coronary heart disease (CHD) all had stronger associations with global cognitive decline in women than in men.

“All men and women should be treated for cardiovascular risk factors and conditions, but this study really highlights the importance of very early and perhaps more aggressive treatment in women with these conditions,” co-investigator Michelle M. Mielke, PhD, professor of epidemiology and neurology, Mayo Clinic, Rochester, Minn., told this news organization.

The findings were published online Jan. 5 in Neurology.
 

Assessing sex differences

Most previous studies in this area have focused on CV risk factors in midlife in relation to late-life dementia (after age 75) or on late-life vascular risk factors and late-life dementia, Dr. Mielke noted.

However, a few recent studies have suggested vascular risk factors can affect cognition even in midlife. The current investigators sought to determine whether there are sex differences in these associations.

They assessed 1,857 nondemented participants aged 50 to 69 years from the Mayo Clinic Study on Aging. The mean education level was 14.9 years, and the mean body mass index (BMI) was 29.7.

Among the participants, 78.9% had at least one CV condition or risk factor, and the proportion was higher in men than women (83.4% vs. 74.5%; P < .0001).

Frequency of each individual CV condition or risk factor was also higher in men than women, and they had more years of education and higher BMI but took fewer medications.

Every 15 months, participants had an in-person interview and physical examination that included a neurologic assessment and short test of memory.

The neuropsychological battery included nine tests across four domains: memory, language, executive function, and visuospatial skills. Researchers calculated z-scores for these domains and for global cognition.
 

Multiple cognitive domains

Whereas this study evaluated multiple cognitive domains, most previous research has focused on global cognitive decline and/or decline in only one or two cognitive domains, the investigators note.

They collected information from medical records on CV conditions such as CHD, arrhythmias, congestive heart failure, peripheral vascular disease (PVD), and stroke; and CV risk factors such as hypertension, diabetes, dyslipidemia, smoking status, and BMI.

Because of the small number of patients with stroke and PVD, these were classified as “other cardiovascular conditions” in the statistical analysis.

Researchers adjusted for sex, age, years of education, depressive symptoms, comorbidities, medications, and apolipoprotein E (APOE) genotyping. The mean follow-up was 3 years and did not differ by sex.

As some participants didn’t have a follow-up visit, the current analysis included 1,394 individuals. Those without follow-up visits were younger, had less education and more comorbidities, and took more medications compared with those with a follow-up.

Results showed most CV conditions were more strongly associated with cognitive function among women than men. For example, CHD was associated with global decline only in women (P < .05).

CHD, diabetes, and dyslipidemia were associated with language decline in women only (all, P < .05), but congestive heart failure was significantly associated with language decline in men only.

Dr. Mielke cautioned about reading too much into the language results for women.

“It’s an intriguing finding and definitely we need to follow up on it,” she said. However, “more studies are needed to examine sex differences before we start saying it only has an effect on language.”
 

‘Treat aggressively and right away’

The researchers were somewhat surprised by the study findings. Because there is a higher prevalence of CV conditions and risk factors in men, they presumed men would be more affected by these conditions, said Dr. Mielke.

“But that’s not what we saw; we saw the reverse. It was actually the women who were affected more by these cardiovascular risk factors and conditions,” she said.

As midlife is when women enter menopause, fluctuating estrogen levels may help explain the differential impact on cognition among women. But Dr. Mielke said she wants to “move beyond” just looking at hormones.

She pointed out there are a variety of psychosocial factors that may also contribute to an imbalance in the cognitive impact of CV conditions on women.

“Midlife is when many women are still taking care of their children at home, are also taking care of their adult parents, and may be undergoing more stress while continuing to do a job,” Dr. Miekle said.

Structural brain development and genetics may also contribute to the greater effect on cognition in women, the investigators note.

Dr. Mielke stressed that the current study only identifies associations. “The next steps are to understand what some of the underlying mechanisms for this are,” she said.

In the meantime, these new results suggest middle-aged women with high blood pressure, cholesterol, or glucose measures “should be treated aggressively and right away” said Dr. Mielke.

“For example, for women who are just starting to become hypertensive, clinicians should treat them right away and not watch and wait.”

Study limitations cited include that its sample was limited to Olmsted County, Minnesota – so results may not be generalized to other populations. Also, as researchers combined PVD and stroke into one group, larger sample sizes are needed, especially for stroke. Another limitation was the study did not have information on duration of all CV conditions or risk factors.
 

Helpful for tailoring interventions?

Commenting on the study, Glen R. Finney, MD, director, Memory and Cognition Program, Geisinger Health Clinic, Wilkes-Barre, Pennsylvania, said the results are important.

“The more we understand about risk factors for the development of Alzheimer’s disease and related dementias, the better we understand how we can reduce the risks,” said Dr. Finney, who was not involved with the research.

Awareness that CV conditions are major risk factors in midlife has been “definitely rising,” said Dr. Finney. “Many studies originally were looking at late life and are now looking more at earlier in the disease process, and I think that’s important.”

Understanding how sex, ethnicity, and other demographic variables affect risks can help to “tailor interventions” for individual patients, he said.

The study was supported by the National Institutes of Health, the GHR Foundation, and the Rochester Epidemiology Project. Dr. Mielke is a consultant for Biogen and Brain Protection Company and is on the editorial boards of Neurology and Alzheimer’s and Dementia. Dr. Finney has reported no relevant financial relationships.

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

Even though men in midlife have more cardiovascular (CV) conditions and risk factors than women of the same age, women are more affected by these conditions in terms of cognitive decline, new research suggests.

Analyses of almost 1,400 participants in the population-based Mayo Clinic Study of Aging showed that diabetes, dyslipidemia, and coronary heart disease (CHD) all had stronger associations with global cognitive decline in women than in men.

“All men and women should be treated for cardiovascular risk factors and conditions, but this study really highlights the importance of very early and perhaps more aggressive treatment in women with these conditions,” co-investigator Michelle M. Mielke, PhD, professor of epidemiology and neurology, Mayo Clinic, Rochester, Minn., told this news organization.

The findings were published online Jan. 5 in Neurology.
 

Assessing sex differences

Most previous studies in this area have focused on CV risk factors in midlife in relation to late-life dementia (after age 75) or on late-life vascular risk factors and late-life dementia, Dr. Mielke noted.

However, a few recent studies have suggested vascular risk factors can affect cognition even in midlife. The current investigators sought to determine whether there are sex differences in these associations.

They assessed 1,857 nondemented participants aged 50 to 69 years from the Mayo Clinic Study on Aging. The mean education level was 14.9 years, and the mean body mass index (BMI) was 29.7.

Among the participants, 78.9% had at least one CV condition or risk factor, and the proportion was higher in men than women (83.4% vs. 74.5%; P < .0001).

Frequency of each individual CV condition or risk factor was also higher in men than women, and they had more years of education and higher BMI but took fewer medications.

Every 15 months, participants had an in-person interview and physical examination that included a neurologic assessment and short test of memory.

The neuropsychological battery included nine tests across four domains: memory, language, executive function, and visuospatial skills. Researchers calculated z-scores for these domains and for global cognition.
 

Multiple cognitive domains

Whereas this study evaluated multiple cognitive domains, most previous research has focused on global cognitive decline and/or decline in only one or two cognitive domains, the investigators note.

They collected information from medical records on CV conditions such as CHD, arrhythmias, congestive heart failure, peripheral vascular disease (PVD), and stroke; and CV risk factors such as hypertension, diabetes, dyslipidemia, smoking status, and BMI.

Because of the small number of patients with stroke and PVD, these were classified as “other cardiovascular conditions” in the statistical analysis.

Researchers adjusted for sex, age, years of education, depressive symptoms, comorbidities, medications, and apolipoprotein E (APOE) genotyping. The mean follow-up was 3 years and did not differ by sex.

As some participants didn’t have a follow-up visit, the current analysis included 1,394 individuals. Those without follow-up visits were younger, had less education and more comorbidities, and took more medications compared with those with a follow-up.

Results showed most CV conditions were more strongly associated with cognitive function among women than men. For example, CHD was associated with global decline only in women (P < .05).

CHD, diabetes, and dyslipidemia were associated with language decline in women only (all, P < .05), but congestive heart failure was significantly associated with language decline in men only.

Dr. Mielke cautioned about reading too much into the language results for women.

“It’s an intriguing finding and definitely we need to follow up on it,” she said. However, “more studies are needed to examine sex differences before we start saying it only has an effect on language.”
 

‘Treat aggressively and right away’

The researchers were somewhat surprised by the study findings. Because there is a higher prevalence of CV conditions and risk factors in men, they presumed men would be more affected by these conditions, said Dr. Mielke.

“But that’s not what we saw; we saw the reverse. It was actually the women who were affected more by these cardiovascular risk factors and conditions,” she said.

As midlife is when women enter menopause, fluctuating estrogen levels may help explain the differential impact on cognition among women. But Dr. Mielke said she wants to “move beyond” just looking at hormones.

She pointed out there are a variety of psychosocial factors that may also contribute to an imbalance in the cognitive impact of CV conditions on women.

“Midlife is when many women are still taking care of their children at home, are also taking care of their adult parents, and may be undergoing more stress while continuing to do a job,” Dr. Miekle said.

Structural brain development and genetics may also contribute to the greater effect on cognition in women, the investigators note.

Dr. Mielke stressed that the current study only identifies associations. “The next steps are to understand what some of the underlying mechanisms for this are,” she said.

In the meantime, these new results suggest middle-aged women with high blood pressure, cholesterol, or glucose measures “should be treated aggressively and right away” said Dr. Mielke.

“For example, for women who are just starting to become hypertensive, clinicians should treat them right away and not watch and wait.”

Study limitations cited include that its sample was limited to Olmsted County, Minnesota – so results may not be generalized to other populations. Also, as researchers combined PVD and stroke into one group, larger sample sizes are needed, especially for stroke. Another limitation was the study did not have information on duration of all CV conditions or risk factors.
 

Helpful for tailoring interventions?

Commenting on the study, Glen R. Finney, MD, director, Memory and Cognition Program, Geisinger Health Clinic, Wilkes-Barre, Pennsylvania, said the results are important.

“The more we understand about risk factors for the development of Alzheimer’s disease and related dementias, the better we understand how we can reduce the risks,” said Dr. Finney, who was not involved with the research.

Awareness that CV conditions are major risk factors in midlife has been “definitely rising,” said Dr. Finney. “Many studies originally were looking at late life and are now looking more at earlier in the disease process, and I think that’s important.”

Understanding how sex, ethnicity, and other demographic variables affect risks can help to “tailor interventions” for individual patients, he said.

The study was supported by the National Institutes of Health, the GHR Foundation, and the Rochester Epidemiology Project. Dr. Mielke is a consultant for Biogen and Brain Protection Company and is on the editorial boards of Neurology and Alzheimer’s and Dementia. Dr. Finney has reported no relevant financial relationships.

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

Even though men in midlife have more cardiovascular (CV) conditions and risk factors than women of the same age, women are more affected by these conditions in terms of cognitive decline, new research suggests.

Analyses of almost 1,400 participants in the population-based Mayo Clinic Study of Aging showed that diabetes, dyslipidemia, and coronary heart disease (CHD) all had stronger associations with global cognitive decline in women than in men.

“All men and women should be treated for cardiovascular risk factors and conditions, but this study really highlights the importance of very early and perhaps more aggressive treatment in women with these conditions,” co-investigator Michelle M. Mielke, PhD, professor of epidemiology and neurology, Mayo Clinic, Rochester, Minn., told this news organization.

The findings were published online Jan. 5 in Neurology.
 

Assessing sex differences

Most previous studies in this area have focused on CV risk factors in midlife in relation to late-life dementia (after age 75) or on late-life vascular risk factors and late-life dementia, Dr. Mielke noted.

However, a few recent studies have suggested vascular risk factors can affect cognition even in midlife. The current investigators sought to determine whether there are sex differences in these associations.

They assessed 1,857 nondemented participants aged 50 to 69 years from the Mayo Clinic Study on Aging. The mean education level was 14.9 years, and the mean body mass index (BMI) was 29.7.

Among the participants, 78.9% had at least one CV condition or risk factor, and the proportion was higher in men than women (83.4% vs. 74.5%; P < .0001).

Frequency of each individual CV condition or risk factor was also higher in men than women, and they had more years of education and higher BMI but took fewer medications.

Every 15 months, participants had an in-person interview and physical examination that included a neurologic assessment and short test of memory.

The neuropsychological battery included nine tests across four domains: memory, language, executive function, and visuospatial skills. Researchers calculated z-scores for these domains and for global cognition.
 

Multiple cognitive domains

Whereas this study evaluated multiple cognitive domains, most previous research has focused on global cognitive decline and/or decline in only one or two cognitive domains, the investigators note.

They collected information from medical records on CV conditions such as CHD, arrhythmias, congestive heart failure, peripheral vascular disease (PVD), and stroke; and CV risk factors such as hypertension, diabetes, dyslipidemia, smoking status, and BMI.

Because of the small number of patients with stroke and PVD, these were classified as “other cardiovascular conditions” in the statistical analysis.

Researchers adjusted for sex, age, years of education, depressive symptoms, comorbidities, medications, and apolipoprotein E (APOE) genotyping. The mean follow-up was 3 years and did not differ by sex.

As some participants didn’t have a follow-up visit, the current analysis included 1,394 individuals. Those without follow-up visits were younger, had less education and more comorbidities, and took more medications compared with those with a follow-up.

Results showed most CV conditions were more strongly associated with cognitive function among women than men. For example, CHD was associated with global decline only in women (P < .05).

CHD, diabetes, and dyslipidemia were associated with language decline in women only (all, P < .05), but congestive heart failure was significantly associated with language decline in men only.

Dr. Mielke cautioned about reading too much into the language results for women.

“It’s an intriguing finding and definitely we need to follow up on it,” she said. However, “more studies are needed to examine sex differences before we start saying it only has an effect on language.”
 

‘Treat aggressively and right away’

The researchers were somewhat surprised by the study findings. Because there is a higher prevalence of CV conditions and risk factors in men, they presumed men would be more affected by these conditions, said Dr. Mielke.

“But that’s not what we saw; we saw the reverse. It was actually the women who were affected more by these cardiovascular risk factors and conditions,” she said.

As midlife is when women enter menopause, fluctuating estrogen levels may help explain the differential impact on cognition among women. But Dr. Mielke said she wants to “move beyond” just looking at hormones.

She pointed out there are a variety of psychosocial factors that may also contribute to an imbalance in the cognitive impact of CV conditions on women.

“Midlife is when many women are still taking care of their children at home, are also taking care of their adult parents, and may be undergoing more stress while continuing to do a job,” Dr. Miekle said.

Structural brain development and genetics may also contribute to the greater effect on cognition in women, the investigators note.

Dr. Mielke stressed that the current study only identifies associations. “The next steps are to understand what some of the underlying mechanisms for this are,” she said.

In the meantime, these new results suggest middle-aged women with high blood pressure, cholesterol, or glucose measures “should be treated aggressively and right away” said Dr. Mielke.

“For example, for women who are just starting to become hypertensive, clinicians should treat them right away and not watch and wait.”

Study limitations cited include that its sample was limited to Olmsted County, Minnesota – so results may not be generalized to other populations. Also, as researchers combined PVD and stroke into one group, larger sample sizes are needed, especially for stroke. Another limitation was the study did not have information on duration of all CV conditions or risk factors.
 

Helpful for tailoring interventions?

Commenting on the study, Glen R. Finney, MD, director, Memory and Cognition Program, Geisinger Health Clinic, Wilkes-Barre, Pennsylvania, said the results are important.

“The more we understand about risk factors for the development of Alzheimer’s disease and related dementias, the better we understand how we can reduce the risks,” said Dr. Finney, who was not involved with the research.

Awareness that CV conditions are major risk factors in midlife has been “definitely rising,” said Dr. Finney. “Many studies originally were looking at late life and are now looking more at earlier in the disease process, and I think that’s important.”

Understanding how sex, ethnicity, and other demographic variables affect risks can help to “tailor interventions” for individual patients, he said.

The study was supported by the National Institutes of Health, the GHR Foundation, and the Rochester Epidemiology Project. Dr. Mielke is a consultant for Biogen and Brain Protection Company and is on the editorial boards of Neurology and Alzheimer’s and Dementia. Dr. Finney has reported no relevant financial relationships.

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

The cardiovascular and cardiometabolic effects of therapy in women with breast cancer vary based on patient factors like weight and menopausal status, according to findings from the Pathways Heart Study recently presented at the San Antonio Breast Cancer Symposium.

Fred Hutchinson Cancer Center

For example, certain chemotherapy drugs may confer higher risk in breast cancer survivors of normal weight, whereas they may lower stroke risk in those who are obese, according to Heather Greenlee, ND, PhD, a public health researcher and naturopathic physician with the Fred Hutchinson Cancer Research Center in Seattle.

In postmenopausal women with breast cancer, aromatase inhibitors may increase cardiovascular risk, while tamoxifen appears to reduce the risk of incident dyslipidemia, she said.

The findings are from separate analyses of data from studies presented during a poster discussion session at the symposium.
 

Breast cancer treatment and cardiovascular effects: The role of weight

In one analysis, Dr. Greenlee and colleagues examined outcomes in 13,582 breast cancer survivors with a median age of 60 years and median follow-up of 7 years to assess whether cardiovascular disease (CVD) risk associated with specific breast cancer therapies varies by body mass index (BMI) category at diagnosis.

Many routinely used breast cancer therapies are cardiotoxic, and being overweight or obese are known risk factors for CVD, but few studies have assessed whether BMI modifies the effect of these treatment on cardiovascular risk, Dr. Greenlee explained.

After adjusting for baseline demographic and health-related factors, and other breast cancer treatment, they found that:

• Ischemic heart disease risk was higher among normal-weight women who received anthracyclines, compared with those who did not (hazard ratio, 4.2). No other risk associations were observed for other breast cancer therapies and BMI groups.
• Heart failure/cardiomyopathy risk was higher among women with normal weight who received anthracyclines, cyclophosphamides, or left-sided radiation, compared with those who did not (HRs, 5.24, 3.27, and 2.05, respectively), and among overweight women who received anthracyclines, compared with those who did not (HR, 2.18). No risk associations were observed for women who received trastuzumab, taxanes, endocrine therapy, or radiation on any side, and no risk associations were observed for women who were obese.
• Stroke risk was higher in normal-weight women who received taxanes, cyclophosphamides, or left-sided radiation versus those who did not (HRs, 2.14, 2.35, and 1.31, respectively), and stroke risk was lower in obese women who received anthracyclines, taxanes, or cyclophosphamide, compared with those who did not (HRs, 0.32, 0.41, and 0.29, respectively). No risk associations were observed for trastuzumab, endocrine therapy, or radiation on any side, and no risk associations were observed for women who were overweight.

The lack of associations noted between treatments and heart failure risk among obese patients could be caused by the “obesity paradox” observed in prior obese populations, the investigators noted, adding that additional analyses are planned to “examine whether different dosage and duration of breast cancer therapy exposures across the BMI groups contributed to these risk associations.”
 

Breast cancer treatment and cardiometabolic effects: The role of menopausal status

In a separate analysis, Dr. Greenlee and colleagues looked at the association between endocrine therapies and cardiometabolic risk based on menopausal status.

Endocrine therapy is associated with CVD in breast cancer survivors and may be associated with developing cardiometabolic risk factors like diabetes, dyslipidemia, and hypertension, they noted, explaining that tamoxifen has mixed estrogenic and antiestrogenic activity, while aromatase inhibitors deplete endogenous estrogen.

Since most studies have compared tamoxifen with aromatase inhibitor use, it has been a challenge challenging to discern the effects of each, Dr. Greenlee said.

She and her colleagues reviewed records for 14,942 breast cancer survivors who were diagnosed between 2005 and 2013. The patients had a mean age of 61 years at baseline, and 24.9% were premenopausal at the time of diagnosis. Of the premenopausal women, 27.3% used tamoxifen, 19.2% used aromatase inhibitors, and 53.5% did not use endocrine therapy, and of the postmenopausal women, 6.6% used tamoxifen, 47.7% used aromatase inhibitors, and 45.7% did not use endocrine therapy.

After adjusting for baseline demographics and health factors, the investigators found that:

• The use of tamoxifen or aromatase inhibitors was not associated with a risk of developing diabetes, dyslipidemia, or hypertension in premenopausal women, or with a risk of developing diabetes or hypertension in postmenopausal women.
• The risk of dyslipidemia was higher in postmenopausal aromatase inhibitor users, and lower in postmenopausal tamoxifen users, compared with postmenopausal non-users of endocrine therapy (HRs, 1.15 and 0.75, respectively).

The lack of associations between endocrine therapy and CVD risk in premenopausal women may be from low power, Dr. Greenlee said, noting that analyses in larger sample sizes are needed.

She and her colleagues plan to conduct further analyses looking at treatment dosage and duration, and comparing steroidal versus nonsteroidal aromatase inhibitors.

Future studies should examine the implications of these associations on long-term CVD and how best to manage lipid profiles in postmenopausal breast cancer survivors who have a history of endocrine therapy treatment, they concluded.

This research was funded by grants from the National Cancer Institute.

[email protected]

The cardiovascular and cardiometabolic effects of therapy in women with breast cancer vary based on patient factors like weight and menopausal status, according to findings from the Pathways Heart Study recently presented at the San Antonio Breast Cancer Symposium.

Fred Hutchinson Cancer Center

For example, certain chemotherapy drugs may confer higher risk in breast cancer survivors of normal weight, whereas they may lower stroke risk in those who are obese, according to Heather Greenlee, ND, PhD, a public health researcher and naturopathic physician with the Fred Hutchinson Cancer Research Center in Seattle.

In postmenopausal women with breast cancer, aromatase inhibitors may increase cardiovascular risk, while tamoxifen appears to reduce the risk of incident dyslipidemia, she said.

The findings are from separate analyses of data from studies presented during a poster discussion session at the symposium.
 

Breast cancer treatment and cardiovascular effects: The role of weight

In one analysis, Dr. Greenlee and colleagues examined outcomes in 13,582 breast cancer survivors with a median age of 60 years and median follow-up of 7 years to assess whether cardiovascular disease (CVD) risk associated with specific breast cancer therapies varies by body mass index (BMI) category at diagnosis.

Many routinely used breast cancer therapies are cardiotoxic, and being overweight or obese are known risk factors for CVD, but few studies have assessed whether BMI modifies the effect of these treatment on cardiovascular risk, Dr. Greenlee explained.

After adjusting for baseline demographic and health-related factors, and other breast cancer treatment, they found that:

• Ischemic heart disease risk was higher among normal-weight women who received anthracyclines, compared with those who did not (hazard ratio, 4.2). No other risk associations were observed for other breast cancer therapies and BMI groups.
• Heart failure/cardiomyopathy risk was higher among women with normal weight who received anthracyclines, cyclophosphamides, or left-sided radiation, compared with those who did not (HRs, 5.24, 3.27, and 2.05, respectively), and among overweight women who received anthracyclines, compared with those who did not (HR, 2.18). No risk associations were observed for women who received trastuzumab, taxanes, endocrine therapy, or radiation on any side, and no risk associations were observed for women who were obese.
• Stroke risk was higher in normal-weight women who received taxanes, cyclophosphamides, or left-sided radiation versus those who did not (HRs, 2.14, 2.35, and 1.31, respectively), and stroke risk was lower in obese women who received anthracyclines, taxanes, or cyclophosphamide, compared with those who did not (HRs, 0.32, 0.41, and 0.29, respectively). No risk associations were observed for trastuzumab, endocrine therapy, or radiation on any side, and no risk associations were observed for women who were overweight.

The lack of associations noted between treatments and heart failure risk among obese patients could be caused by the “obesity paradox” observed in prior obese populations, the investigators noted, adding that additional analyses are planned to “examine whether different dosage and duration of breast cancer therapy exposures across the BMI groups contributed to these risk associations.”
 

Breast cancer treatment and cardiometabolic effects: The role of menopausal status

In a separate analysis, Dr. Greenlee and colleagues looked at the association between endocrine therapies and cardiometabolic risk based on menopausal status.

Endocrine therapy is associated with CVD in breast cancer survivors and may be associated with developing cardiometabolic risk factors like diabetes, dyslipidemia, and hypertension, they noted, explaining that tamoxifen has mixed estrogenic and antiestrogenic activity, while aromatase inhibitors deplete endogenous estrogen.

Since most studies have compared tamoxifen with aromatase inhibitor use, it has been a challenge challenging to discern the effects of each, Dr. Greenlee said.

She and her colleagues reviewed records for 14,942 breast cancer survivors who were diagnosed between 2005 and 2013. The patients had a mean age of 61 years at baseline, and 24.9% were premenopausal at the time of diagnosis. Of the premenopausal women, 27.3% used tamoxifen, 19.2% used aromatase inhibitors, and 53.5% did not use endocrine therapy, and of the postmenopausal women, 6.6% used tamoxifen, 47.7% used aromatase inhibitors, and 45.7% did not use endocrine therapy.

After adjusting for baseline demographics and health factors, the investigators found that:

• The use of tamoxifen or aromatase inhibitors was not associated with a risk of developing diabetes, dyslipidemia, or hypertension in premenopausal women, or with a risk of developing diabetes or hypertension in postmenopausal women.
• The risk of dyslipidemia was higher in postmenopausal aromatase inhibitor users, and lower in postmenopausal tamoxifen users, compared with postmenopausal non-users of endocrine therapy (HRs, 1.15 and 0.75, respectively).

The lack of associations between endocrine therapy and CVD risk in premenopausal women may be from low power, Dr. Greenlee said, noting that analyses in larger sample sizes are needed.

She and her colleagues plan to conduct further analyses looking at treatment dosage and duration, and comparing steroidal versus nonsteroidal aromatase inhibitors.

Future studies should examine the implications of these associations on long-term CVD and how best to manage lipid profiles in postmenopausal breast cancer survivors who have a history of endocrine therapy treatment, they concluded.

This research was funded by grants from the National Cancer Institute.

[email protected]

The cardiovascular and cardiometabolic effects of therapy in women with breast cancer vary based on patient factors like weight and menopausal status, according to findings from the Pathways Heart Study recently presented at the San Antonio Breast Cancer Symposium.

Fred Hutchinson Cancer Center

For example, certain chemotherapy drugs may confer higher risk in breast cancer survivors of normal weight, whereas they may lower stroke risk in those who are obese, according to Heather Greenlee, ND, PhD, a public health researcher and naturopathic physician with the Fred Hutchinson Cancer Research Center in Seattle.

In postmenopausal women with breast cancer, aromatase inhibitors may increase cardiovascular risk, while tamoxifen appears to reduce the risk of incident dyslipidemia, she said.

The findings are from separate analyses of data from studies presented during a poster discussion session at the symposium.
 

Breast cancer treatment and cardiovascular effects: The role of weight

In one analysis, Dr. Greenlee and colleagues examined outcomes in 13,582 breast cancer survivors with a median age of 60 years and median follow-up of 7 years to assess whether cardiovascular disease (CVD) risk associated with specific breast cancer therapies varies by body mass index (BMI) category at diagnosis.

Many routinely used breast cancer therapies are cardiotoxic, and being overweight or obese are known risk factors for CVD, but few studies have assessed whether BMI modifies the effect of these treatment on cardiovascular risk, Dr. Greenlee explained.

After adjusting for baseline demographic and health-related factors, and other breast cancer treatment, they found that:

• Ischemic heart disease risk was higher among normal-weight women who received anthracyclines, compared with those who did not (hazard ratio, 4.2). No other risk associations were observed for other breast cancer therapies and BMI groups.
• Heart failure/cardiomyopathy risk was higher among women with normal weight who received anthracyclines, cyclophosphamides, or left-sided radiation, compared with those who did not (HRs, 5.24, 3.27, and 2.05, respectively), and among overweight women who received anthracyclines, compared with those who did not (HR, 2.18). No risk associations were observed for women who received trastuzumab, taxanes, endocrine therapy, or radiation on any side, and no risk associations were observed for women who were obese.
• Stroke risk was higher in normal-weight women who received taxanes, cyclophosphamides, or left-sided radiation versus those who did not (HRs, 2.14, 2.35, and 1.31, respectively), and stroke risk was lower in obese women who received anthracyclines, taxanes, or cyclophosphamide, compared with those who did not (HRs, 0.32, 0.41, and 0.29, respectively). No risk associations were observed for trastuzumab, endocrine therapy, or radiation on any side, and no risk associations were observed for women who were overweight.

The lack of associations noted between treatments and heart failure risk among obese patients could be caused by the “obesity paradox” observed in prior obese populations, the investigators noted, adding that additional analyses are planned to “examine whether different dosage and duration of breast cancer therapy exposures across the BMI groups contributed to these risk associations.”
 

Breast cancer treatment and cardiometabolic effects: The role of menopausal status

In a separate analysis, Dr. Greenlee and colleagues looked at the association between endocrine therapies and cardiometabolic risk based on menopausal status.

Endocrine therapy is associated with CVD in breast cancer survivors and may be associated with developing cardiometabolic risk factors like diabetes, dyslipidemia, and hypertension, they noted, explaining that tamoxifen has mixed estrogenic and antiestrogenic activity, while aromatase inhibitors deplete endogenous estrogen.

Since most studies have compared tamoxifen with aromatase inhibitor use, it has been a challenge challenging to discern the effects of each, Dr. Greenlee said.

She and her colleagues reviewed records for 14,942 breast cancer survivors who were diagnosed between 2005 and 2013. The patients had a mean age of 61 years at baseline, and 24.9% were premenopausal at the time of diagnosis. Of the premenopausal women, 27.3% used tamoxifen, 19.2% used aromatase inhibitors, and 53.5% did not use endocrine therapy, and of the postmenopausal women, 6.6% used tamoxifen, 47.7% used aromatase inhibitors, and 45.7% did not use endocrine therapy.

After adjusting for baseline demographics and health factors, the investigators found that:

• The use of tamoxifen or aromatase inhibitors was not associated with a risk of developing diabetes, dyslipidemia, or hypertension in premenopausal women, or with a risk of developing diabetes or hypertension in postmenopausal women.
• The risk of dyslipidemia was higher in postmenopausal aromatase inhibitor users, and lower in postmenopausal tamoxifen users, compared with postmenopausal non-users of endocrine therapy (HRs, 1.15 and 0.75, respectively).

The lack of associations between endocrine therapy and CVD risk in premenopausal women may be from low power, Dr. Greenlee said, noting that analyses in larger sample sizes are needed.

She and her colleagues plan to conduct further analyses looking at treatment dosage and duration, and comparing steroidal versus nonsteroidal aromatase inhibitors.

Future studies should examine the implications of these associations on long-term CVD and how best to manage lipid profiles in postmenopausal breast cancer survivors who have a history of endocrine therapy treatment, they concluded.

This research was funded by grants from the National Cancer Institute.

[email protected]

Women whose ovaries were surgically removed before the age of 46 had a higher risk of mild cognitive impairment (MCI) around 30 years later, compared with those who did not undergo bilateral oophorectomy, according to a population-based linkage study published in JAMA Network Open.

The findings suggest that “physicians treating women with premenopausal bilateral oophorectomy need to be aware of their patients’ risk of cognitive impairment or MCI and should consider implementing treatment-monitoring plans,” noted lead author Walter A. Rocca, MD, MPH, from the division of epidemiology, department of quantitative health sciences, at the Mayo Clinic, Rochester, Minn. and colleagues.

The results may particularly “help women at mean risk levels of ovarian cancer to better evaluate the risk-to-benefit ratio of undergoing bilateral oophorectomy prior to spontaneous menopause for the prevention of ovarian cancer,” they emphasized.

While the link between premenopausal bilateral oophorectomy and higher risk of cognitive impairment has been previously suggested, this new study “contributes valuable new data to a major public health importance issue and addresses a number of important shortcomings of existing literature,” Marios K. Georgakis, MD, PhD, and Eleni T. Petridou, MD, PhD, noted in an accompanying commentary.

“As bilateral oophorectomy is still a common procedure at least in well-resourced countries, the results of these studies should alert clinicians about its potential public health consequences. Given that the abrupt cessation of ovarian hormones might be accompanied by previously underestimated long-term adverse effects, treating physicians proposing the operation should weigh its benefits against potential long-term harmful effects, especially among women without an absolute indication,” noted Dr. Georgakis and Dr. Petridou, respectively from the Center for Genomic Medicine at Massachusetts General Hospital in Boston and the National and Kapodistrian University of Athens.

The case-control cross-sectional study used data from the Mayo Clinic Study of Aging (MCSA), a prospective, population-based study examining risk factors for, as well as prevalence and incidence of cognitive decline and MCI among a representative sample of women in Olmsted County, Minn. It included 2,732 women aged 50-89 years who participated in the MCSA study from 2004 to 2019 and underwent a clinical evaluation and comprehensive cognitive testing including nine tests covering four cognitive domains. Almost all of the subjects (98.4%) were White. The mean age of cognitive evaluation was 74 years – at which time 283 women (10.4%) were diagnosed with MCI (197 with amnestic and 86 with nonamnestic MCI). Data from the Rochester Epidemiology Project medical record–linkage system showed a total of 625 women (22.9%) had a history of bilateral oophorectomy. Among this group, 161 women underwent the procedure both before age 46, and before menopause, with 46 (28.6%) receiving oral conjugated equine estrogen (unopposed) and the remaining 95 (59.0%) receiving no estrogen therapy.

The study found that, compared with women who did not undergo bilateral oophorectomy, those who did so before age 46, but not after this age, had statistically significantly increased odds of MCI (adjusted odds ratio, 2.21; P < .001). When type of MCI was examined, the risk was statistically significant for nonamnestic MCI (aOR, 2.96; P < .001), and amnestic (aOR, 1.87; P =.03). The study also found no evidence that estrogen therapy was associated with decreased risk of MCI among women aged less than 46 years, with an aOR of 2.56 in those who received estrogen therapy and 2.05 in those who did not (P = .01 for both).

Finally, in women who had bilateral oophorectomy before menopause and before age 50, surgical indication for the procedure affected the association with MCI. Indications of either cancer or “no ovarian condition” (i.e., performed at the time of hysterectomy) were associated with no increased risk, whereas there was a statistically significantly increased risk associated with benign indications such as an adnexal mass, cyst or endometriosis (aOR, 2.43; P = .003). “This is important,” noted the commentators, “because in many of those cases removal of both ovaries could be avoided.”

The study also found that, compared with women who had not undergone bilateral oophorectomy, those who had also had increased frequency of cardiovascular risk factors, heart disease, and stroke at the time of their cognitive evaluation. “Additional research is needed to clarify the biological explanation of the association,” the investigators said.

The prevailing hypothesis for why premenopausal bilateral oophorectomy is associated with cognitive decline “is that the abrupt endocrine cessation of exposure to ovarian hormones accelerates the aging process,” the commentators noted. “Most important from a clinical perspective is whether these women would benefit from specific hormone replacement therapy schemes. Observational studies cannot reliably answer this question, and possibly it is time to rethink designing trials in specific groups of women who underwent bilateral oophorectomy before 46 years of age starting treatment immediately thereafter.”

In an interview Dr. Georgakis elaborated on this point, saying that, while the Women’s Health Study clearly showed no benefit of hormone replacement therapy for preventing dementia, it recruited women who were aged 65 years or older and had therefore undergone menopause more than 10-15 years earlier. “A hypothesis suggests that a critical vulnerability window exists shortly after menopause during which hormone replacement therapy might be needed to ameliorate any elevated risk,” he said. “Thus, it might make sense to reconsider a trial focused on this group of premenopausal women, who need to undergo oophorectomy at a young age (<46 years). Early initiation would be important. Unfortunately, such a trial would be difficult to conduct, because these women would need to be followed up for very long periods, as cognitive decline usually does not occur before the age of 65.”

Asked to comment on the study, Meadow Good, DO, an ob.gyn., female pelvic medicine and reconstructive surgeon, and physician adviser for Winnie Palmer Hospital for Women & Babies in Orlando, said this study adds credibility to previous studies showing the cognitive risk associated with premenopausal bilateral oophorectomy. “The literature is now pointing to a need to refrain from elective bilateral oophorectomy in women less than 60,” she said in an interview. “It should not be common that a women receives a bilateral oophorectomy before 60 for benign reasons.”

She added that cognition is not the only think at stake. “Bilateral oophorectomy before the age of 60 has a higher risk of incident heart disease, stroke, lung cancer and total cancers,” she said, citing a prospective cohort study within the Nurses’ Health Study.

Dr. Rocca reported financial support from the Mayo Clinic Research Committee during the conduct of the study. One coauthor reported unrestricted grants from Biogen and consulting fees from Brain Protection outside the submitted work. No other disclosures were reported from the authors. Dr. Georgakis, Dr. Petridou, and Dr. Good reported no conflicts of interest. The study was funded by the National Institute on Aging. It also used resources of the Rochester Epidemiology Project medical record–linkage system, which is supported by the NIA, the Mayo Clinic Research Committee, and user fees. Dr. Rocca was partly funded by the Ralph S. and Beverley E. Caulkins Professorship of Neurodegenerative Diseases Research of the Mayo Clinic.

Women whose ovaries were surgically removed before the age of 46 had a higher risk of mild cognitive impairment (MCI) around 30 years later, compared with those who did not undergo bilateral oophorectomy, according to a population-based linkage study published in JAMA Network Open.

The findings suggest that “physicians treating women with premenopausal bilateral oophorectomy need to be aware of their patients’ risk of cognitive impairment or MCI and should consider implementing treatment-monitoring plans,” noted lead author Walter A. Rocca, MD, MPH, from the division of epidemiology, department of quantitative health sciences, at the Mayo Clinic, Rochester, Minn. and colleagues.

The results may particularly “help women at mean risk levels of ovarian cancer to better evaluate the risk-to-benefit ratio of undergoing bilateral oophorectomy prior to spontaneous menopause for the prevention of ovarian cancer,” they emphasized.

While the link between premenopausal bilateral oophorectomy and higher risk of cognitive impairment has been previously suggested, this new study “contributes valuable new data to a major public health importance issue and addresses a number of important shortcomings of existing literature,” Marios K. Georgakis, MD, PhD, and Eleni T. Petridou, MD, PhD, noted in an accompanying commentary.

“As bilateral oophorectomy is still a common procedure at least in well-resourced countries, the results of these studies should alert clinicians about its potential public health consequences. Given that the abrupt cessation of ovarian hormones might be accompanied by previously underestimated long-term adverse effects, treating physicians proposing the operation should weigh its benefits against potential long-term harmful effects, especially among women without an absolute indication,” noted Dr. Georgakis and Dr. Petridou, respectively from the Center for Genomic Medicine at Massachusetts General Hospital in Boston and the National and Kapodistrian University of Athens.

The case-control cross-sectional study used data from the Mayo Clinic Study of Aging (MCSA), a prospective, population-based study examining risk factors for, as well as prevalence and incidence of cognitive decline and MCI among a representative sample of women in Olmsted County, Minn. It included 2,732 women aged 50-89 years who participated in the MCSA study from 2004 to 2019 and underwent a clinical evaluation and comprehensive cognitive testing including nine tests covering four cognitive domains. Almost all of the subjects (98.4%) were White. The mean age of cognitive evaluation was 74 years – at which time 283 women (10.4%) were diagnosed with MCI (197 with amnestic and 86 with nonamnestic MCI). Data from the Rochester Epidemiology Project medical record–linkage system showed a total of 625 women (22.9%) had a history of bilateral oophorectomy. Among this group, 161 women underwent the procedure both before age 46, and before menopause, with 46 (28.6%) receiving oral conjugated equine estrogen (unopposed) and the remaining 95 (59.0%) receiving no estrogen therapy.

The study found that, compared with women who did not undergo bilateral oophorectomy, those who did so before age 46, but not after this age, had statistically significantly increased odds of MCI (adjusted odds ratio, 2.21; P < .001). When type of MCI was examined, the risk was statistically significant for nonamnestic MCI (aOR, 2.96; P < .001), and amnestic (aOR, 1.87; P =.03). The study also found no evidence that estrogen therapy was associated with decreased risk of MCI among women aged less than 46 years, with an aOR of 2.56 in those who received estrogen therapy and 2.05 in those who did not (P = .01 for both).

Finally, in women who had bilateral oophorectomy before menopause and before age 50, surgical indication for the procedure affected the association with MCI. Indications of either cancer or “no ovarian condition” (i.e., performed at the time of hysterectomy) were associated with no increased risk, whereas there was a statistically significantly increased risk associated with benign indications such as an adnexal mass, cyst or endometriosis (aOR, 2.43; P = .003). “This is important,” noted the commentators, “because in many of those cases removal of both ovaries could be avoided.”

The study also found that, compared with women who had not undergone bilateral oophorectomy, those who had also had increased frequency of cardiovascular risk factors, heart disease, and stroke at the time of their cognitive evaluation. “Additional research is needed to clarify the biological explanation of the association,” the investigators said.

The prevailing hypothesis for why premenopausal bilateral oophorectomy is associated with cognitive decline “is that the abrupt endocrine cessation of exposure to ovarian hormones accelerates the aging process,” the commentators noted. “Most important from a clinical perspective is whether these women would benefit from specific hormone replacement therapy schemes. Observational studies cannot reliably answer this question, and possibly it is time to rethink designing trials in specific groups of women who underwent bilateral oophorectomy before 46 years of age starting treatment immediately thereafter.”

In an interview Dr. Georgakis elaborated on this point, saying that, while the Women’s Health Study clearly showed no benefit of hormone replacement therapy for preventing dementia, it recruited women who were aged 65 years or older and had therefore undergone menopause more than 10-15 years earlier. “A hypothesis suggests that a critical vulnerability window exists shortly after menopause during which hormone replacement therapy might be needed to ameliorate any elevated risk,” he said. “Thus, it might make sense to reconsider a trial focused on this group of premenopausal women, who need to undergo oophorectomy at a young age (<46 years). Early initiation would be important. Unfortunately, such a trial would be difficult to conduct, because these women would need to be followed up for very long periods, as cognitive decline usually does not occur before the age of 65.”

Asked to comment on the study, Meadow Good, DO, an ob.gyn., female pelvic medicine and reconstructive surgeon, and physician adviser for Winnie Palmer Hospital for Women & Babies in Orlando, said this study adds credibility to previous studies showing the cognitive risk associated with premenopausal bilateral oophorectomy. “The literature is now pointing to a need to refrain from elective bilateral oophorectomy in women less than 60,” she said in an interview. “It should not be common that a women receives a bilateral oophorectomy before 60 for benign reasons.”

She added that cognition is not the only think at stake. “Bilateral oophorectomy before the age of 60 has a higher risk of incident heart disease, stroke, lung cancer and total cancers,” she said, citing a prospective cohort study within the Nurses’ Health Study.

Dr. Rocca reported financial support from the Mayo Clinic Research Committee during the conduct of the study. One coauthor reported unrestricted grants from Biogen and consulting fees from Brain Protection outside the submitted work. No other disclosures were reported from the authors. Dr. Georgakis, Dr. Petridou, and Dr. Good reported no conflicts of interest. The study was funded by the National Institute on Aging. It also used resources of the Rochester Epidemiology Project medical record–linkage system, which is supported by the NIA, the Mayo Clinic Research Committee, and user fees. Dr. Rocca was partly funded by the Ralph S. and Beverley E. Caulkins Professorship of Neurodegenerative Diseases Research of the Mayo Clinic.

Women whose ovaries were surgically removed before the age of 46 had a higher risk of mild cognitive impairment (MCI) around 30 years later, compared with those who did not undergo bilateral oophorectomy, according to a population-based linkage study published in JAMA Network Open.

The findings suggest that “physicians treating women with premenopausal bilateral oophorectomy need to be aware of their patients’ risk of cognitive impairment or MCI and should consider implementing treatment-monitoring plans,” noted lead author Walter A. Rocca, MD, MPH, from the division of epidemiology, department of quantitative health sciences, at the Mayo Clinic, Rochester, Minn. and colleagues.

The results may particularly “help women at mean risk levels of ovarian cancer to better evaluate the risk-to-benefit ratio of undergoing bilateral oophorectomy prior to spontaneous menopause for the prevention of ovarian cancer,” they emphasized.

While the link between premenopausal bilateral oophorectomy and higher risk of cognitive impairment has been previously suggested, this new study “contributes valuable new data to a major public health importance issue and addresses a number of important shortcomings of existing literature,” Marios K. Georgakis, MD, PhD, and Eleni T. Petridou, MD, PhD, noted in an accompanying commentary.

“As bilateral oophorectomy is still a common procedure at least in well-resourced countries, the results of these studies should alert clinicians about its potential public health consequences. Given that the abrupt cessation of ovarian hormones might be accompanied by previously underestimated long-term adverse effects, treating physicians proposing the operation should weigh its benefits against potential long-term harmful effects, especially among women without an absolute indication,” noted Dr. Georgakis and Dr. Petridou, respectively from the Center for Genomic Medicine at Massachusetts General Hospital in Boston and the National and Kapodistrian University of Athens.

The case-control cross-sectional study used data from the Mayo Clinic Study of Aging (MCSA), a prospective, population-based study examining risk factors for, as well as prevalence and incidence of cognitive decline and MCI among a representative sample of women in Olmsted County, Minn. It included 2,732 women aged 50-89 years who participated in the MCSA study from 2004 to 2019 and underwent a clinical evaluation and comprehensive cognitive testing including nine tests covering four cognitive domains. Almost all of the subjects (98.4%) were White. The mean age of cognitive evaluation was 74 years – at which time 283 women (10.4%) were diagnosed with MCI (197 with amnestic and 86 with nonamnestic MCI). Data from the Rochester Epidemiology Project medical record–linkage system showed a total of 625 women (22.9%) had a history of bilateral oophorectomy. Among this group, 161 women underwent the procedure both before age 46, and before menopause, with 46 (28.6%) receiving oral conjugated equine estrogen (unopposed) and the remaining 95 (59.0%) receiving no estrogen therapy.

The study found that, compared with women who did not undergo bilateral oophorectomy, those who did so before age 46, but not after this age, had statistically significantly increased odds of MCI (adjusted odds ratio, 2.21; P < .001). When type of MCI was examined, the risk was statistically significant for nonamnestic MCI (aOR, 2.96; P < .001), and amnestic (aOR, 1.87; P =.03). The study also found no evidence that estrogen therapy was associated with decreased risk of MCI among women aged less than 46 years, with an aOR of 2.56 in those who received estrogen therapy and 2.05 in those who did not (P = .01 for both).

Finally, in women who had bilateral oophorectomy before menopause and before age 50, surgical indication for the procedure affected the association with MCI. Indications of either cancer or “no ovarian condition” (i.e., performed at the time of hysterectomy) were associated with no increased risk, whereas there was a statistically significantly increased risk associated with benign indications such as an adnexal mass, cyst or endometriosis (aOR, 2.43; P = .003). “This is important,” noted the commentators, “because in many of those cases removal of both ovaries could be avoided.”

The study also found that, compared with women who had not undergone bilateral oophorectomy, those who had also had increased frequency of cardiovascular risk factors, heart disease, and stroke at the time of their cognitive evaluation. “Additional research is needed to clarify the biological explanation of the association,” the investigators said.

The prevailing hypothesis for why premenopausal bilateral oophorectomy is associated with cognitive decline “is that the abrupt endocrine cessation of exposure to ovarian hormones accelerates the aging process,” the commentators noted. “Most important from a clinical perspective is whether these women would benefit from specific hormone replacement therapy schemes. Observational studies cannot reliably answer this question, and possibly it is time to rethink designing trials in specific groups of women who underwent bilateral oophorectomy before 46 years of age starting treatment immediately thereafter.”

In an interview Dr. Georgakis elaborated on this point, saying that, while the Women’s Health Study clearly showed no benefit of hormone replacement therapy for preventing dementia, it recruited women who were aged 65 years or older and had therefore undergone menopause more than 10-15 years earlier. “A hypothesis suggests that a critical vulnerability window exists shortly after menopause during which hormone replacement therapy might be needed to ameliorate any elevated risk,” he said. “Thus, it might make sense to reconsider a trial focused on this group of premenopausal women, who need to undergo oophorectomy at a young age (<46 years). Early initiation would be important. Unfortunately, such a trial would be difficult to conduct, because these women would need to be followed up for very long periods, as cognitive decline usually does not occur before the age of 65.”

Asked to comment on the study, Meadow Good, DO, an ob.gyn., female pelvic medicine and reconstructive surgeon, and physician adviser for Winnie Palmer Hospital for Women & Babies in Orlando, said this study adds credibility to previous studies showing the cognitive risk associated with premenopausal bilateral oophorectomy. “The literature is now pointing to a need to refrain from elective bilateral oophorectomy in women less than 60,” she said in an interview. “It should not be common that a women receives a bilateral oophorectomy before 60 for benign reasons.”

She added that cognition is not the only think at stake. “Bilateral oophorectomy before the age of 60 has a higher risk of incident heart disease, stroke, lung cancer and total cancers,” she said, citing a prospective cohort study within the Nurses’ Health Study.

Dr. Rocca reported financial support from the Mayo Clinic Research Committee during the conduct of the study. One coauthor reported unrestricted grants from Biogen and consulting fees from Brain Protection outside the submitted work. No other disclosures were reported from the authors. Dr. Georgakis, Dr. Petridou, and Dr. Good reported no conflicts of interest. The study was funded by the National Institute on Aging. It also used resources of the Rochester Epidemiology Project medical record–linkage system, which is supported by the NIA, the Mayo Clinic Research Committee, and user fees. Dr. Rocca was partly funded by the Ralph S. and Beverley E. Caulkins Professorship of Neurodegenerative Diseases Research of the Mayo Clinic.

Li FG, Maheux-Lacroix S, Deans R, et al. Effect of fractional carbon dioxide laser vs sham treatment on symptom severity in women with postmenopausal vaginal symptoms: a randomized clinical trial. JAMA. 2021;326:1381-1389. doi: 10.1001/jama.2021.14892.

EXPERT COMMENTARY

Symptomatic vaginal atrophy, also referred to as genitourinary syndrome of menopause (GSM), is common and tends to progress without treatment. When use of over-the-counter lubricants and/or moisturizers are not sufficient to address symptoms, vaginal estrogen has represented the mainstay of treatment for this condition and effectively addresses GSM symptoms.¹ In recent years, some physicians have been offering vaginal carbon dioxide (CO2) laser therapy as an alternative to vaginal estrogen in the treatment of GSM; however, the efficacy of laser therapy in this setting has been uncertain.

Li and colleagues conducted a double-blind randomized trial in postmenopausal women with bothersome vaginal symptoms to compare the efficacy of the fractional CO2 vaginal laser with that of sham treatment.

Details of the study

Investigators (who received no funding from any relevant commercial entity) at a teaching hospital in Sydney, Australia, randomly assigned 85 women with menopausal symptoms suggestive of GSM to laser (n = 43) or sham (n = 42) treatment. Participants underwent 3 treatments at monthly intervals. Laser treatments were performed with standard settings (40-watt power), while sham treatments were conducted with low settings that have no tissue effect. Local anesthesia cream was employed for all procedures, and a plume evacuator was used to remove visual and olfactory effects from laser smoke.

To maintain blinding, different clinicians performed assessments and treatments. Symptom severity assessments were based on a visual analog scale (VAS) and the Vulvovaginal Symptom Questionnaire (VSQ), with a minimal clinically important difference specified as a 50% decrease in severity scores of both assessment tools. Change in severity of symptoms, including dyspareunia, dysuria, vaginal dryness, and burning and itching, was assessed at 12 months. Quality of life, the Vaginal Health Index (VHI) score, and vaginal histology were among the secondary outcomes. In addition, vaginal biopsies were performed at baseline and 6 months after study treatment.

Among the 78 women (91.7%) who completed the 12-month evaluations, the mean age was approximately 57, more than 95% were White, and approximately half were sexually active.

Results. For the laser and sham treatment groups, at 12 months no significant differences were noted for change in overall symptoms or in the most severe symptom. Many participants who received laser or sham treatment reported an improvement in vaginal symptoms 12 months following treatment.

The VAS score for a change in symptom severity in the laser-treated group compared with the sham-treated group was -17.2 versus -26.6, a difference of 9.4 (95% confidence interval [CI], -28.6 to 47.5), while the VAS score for the most severe symptom was -24.5 versus -20.4, a difference of -4.1 (95% CI, -32.5 to 24.3). The VSQ score was, respectively, -3.1 versus -1.6 (difference, -1.5 [95% CI, -5.9 to 3.0]). The mean quality of life score showed no significant differences between the laser and the sham group (6.3 vs 1.4, a difference of 4.8 [95% CI, -3.9 to 13.5]). The VHI score was 0.9 in the laser group versus 1.3 in the sham group, for a difference of -0.4 (95% CI, -4.3 to 3.6). Likewise, the proportion of participants who noted a reduction of more than 50% in bother from their most severe symptoms was similar in the 2 groups. Similarly, changes in vaginal histology were similar in the laser and sham groups.

The proportion of participants who reported adverse events, including transient vaginal discomfort, discharge, or urinary tract symptoms, was similar in the 2 groups.

Study strengths and limitations

Although other randomized studies of fractionated laser therapy for GSM have been reported, this Australian trial is the largest and longest to date and also is the first to have used sham-treated controls.

Breast cancer survivors represent a group of patients for whom treatment of GSM can be a major conundrum—induced menopause that often results when combination chemotherapy is employed in premenopausal survivors can result in severe GSM; use of aromatase inhibitors likewise can cause bothersome GSM symptoms. Since the US Food and Drug Administration lists a personal history of breast cancer as a contraindication to use of any estrogen formulation, breast cancer survivors represent a population targeted by physicians offering vaginal laser treatment. Accordingly, that approximately 50% of trial participants were breast cancer survivors means the investigators were assessing the impact of laser therapy in a population of particular clinical relevance. Of note, as with participants overall, laser therapy when employed in breast cancer survivors did not result in outcomes distinct from sham treatments.² ●

Li FG, Maheux-Lacroix S, Deans R, et al. Effect of fractional carbon dioxide laser vs sham treatment on symptom severity in women with postmenopausal vaginal symptoms: a randomized clinical trial. JAMA. 2021;326:1381-1389. doi: 10.1001/jama.2021.14892.

EXPERT COMMENTARY

Symptomatic vaginal atrophy, also referred to as genitourinary syndrome of menopause (GSM), is common and tends to progress without treatment. When use of over-the-counter lubricants and/or moisturizers are not sufficient to address symptoms, vaginal estrogen has represented the mainstay of treatment for this condition and effectively addresses GSM symptoms.¹ In recent years, some physicians have been offering vaginal carbon dioxide (CO2) laser therapy as an alternative to vaginal estrogen in the treatment of GSM; however, the efficacy of laser therapy in this setting has been uncertain.

Li and colleagues conducted a double-blind randomized trial in postmenopausal women with bothersome vaginal symptoms to compare the efficacy of the fractional CO2 vaginal laser with that of sham treatment.

Details of the study

Investigators (who received no funding from any relevant commercial entity) at a teaching hospital in Sydney, Australia, randomly assigned 85 women with menopausal symptoms suggestive of GSM to laser (n = 43) or sham (n = 42) treatment. Participants underwent 3 treatments at monthly intervals. Laser treatments were performed with standard settings (40-watt power), while sham treatments were conducted with low settings that have no tissue effect. Local anesthesia cream was employed for all procedures, and a plume evacuator was used to remove visual and olfactory effects from laser smoke.

To maintain blinding, different clinicians performed assessments and treatments. Symptom severity assessments were based on a visual analog scale (VAS) and the Vulvovaginal Symptom Questionnaire (VSQ), with a minimal clinically important difference specified as a 50% decrease in severity scores of both assessment tools. Change in severity of symptoms, including dyspareunia, dysuria, vaginal dryness, and burning and itching, was assessed at 12 months. Quality of life, the Vaginal Health Index (VHI) score, and vaginal histology were among the secondary outcomes. In addition, vaginal biopsies were performed at baseline and 6 months after study treatment.

Among the 78 women (91.7%) who completed the 12-month evaluations, the mean age was approximately 57, more than 95% were White, and approximately half were sexually active.

Results. For the laser and sham treatment groups, at 12 months no significant differences were noted for change in overall symptoms or in the most severe symptom. Many participants who received laser or sham treatment reported an improvement in vaginal symptoms 12 months following treatment.

The VAS score for a change in symptom severity in the laser-treated group compared with the sham-treated group was -17.2 versus -26.6, a difference of 9.4 (95% confidence interval [CI], -28.6 to 47.5), while the VAS score for the most severe symptom was -24.5 versus -20.4, a difference of -4.1 (95% CI, -32.5 to 24.3). The VSQ score was, respectively, -3.1 versus -1.6 (difference, -1.5 [95% CI, -5.9 to 3.0]). The mean quality of life score showed no significant differences between the laser and the sham group (6.3 vs 1.4, a difference of 4.8 [95% CI, -3.9 to 13.5]). The VHI score was 0.9 in the laser group versus 1.3 in the sham group, for a difference of -0.4 (95% CI, -4.3 to 3.6). Likewise, the proportion of participants who noted a reduction of more than 50% in bother from their most severe symptoms was similar in the 2 groups. Similarly, changes in vaginal histology were similar in the laser and sham groups.

The proportion of participants who reported adverse events, including transient vaginal discomfort, discharge, or urinary tract symptoms, was similar in the 2 groups.

Study strengths and limitations

Although other randomized studies of fractionated laser therapy for GSM have been reported, this Australian trial is the largest and longest to date and also is the first to have used sham-treated controls.

Breast cancer survivors represent a group of patients for whom treatment of GSM can be a major conundrum—induced menopause that often results when combination chemotherapy is employed in premenopausal survivors can result in severe GSM; use of aromatase inhibitors likewise can cause bothersome GSM symptoms. Since the US Food and Drug Administration lists a personal history of breast cancer as a contraindication to use of any estrogen formulation, breast cancer survivors represent a population targeted by physicians offering vaginal laser treatment. Accordingly, that approximately 50% of trial participants were breast cancer survivors means the investigators were assessing the impact of laser therapy in a population of particular clinical relevance. Of note, as with participants overall, laser therapy when employed in breast cancer survivors did not result in outcomes distinct from sham treatments.² ●

Li FG, Maheux-Lacroix S, Deans R, et al. Effect of fractional carbon dioxide laser vs sham treatment on symptom severity in women with postmenopausal vaginal symptoms: a randomized clinical trial. JAMA. 2021;326:1381-1389. doi: 10.1001/jama.2021.14892.

EXPERT COMMENTARY

Symptomatic vaginal atrophy, also referred to as genitourinary syndrome of menopause (GSM), is common and tends to progress without treatment. When use of over-the-counter lubricants and/or moisturizers are not sufficient to address symptoms, vaginal estrogen has represented the mainstay of treatment for this condition and effectively addresses GSM symptoms.¹ In recent years, some physicians have been offering vaginal carbon dioxide (CO2) laser therapy as an alternative to vaginal estrogen in the treatment of GSM; however, the efficacy of laser therapy in this setting has been uncertain.

Li and colleagues conducted a double-blind randomized trial in postmenopausal women with bothersome vaginal symptoms to compare the efficacy of the fractional CO2 vaginal laser with that of sham treatment.

Details of the study

Investigators (who received no funding from any relevant commercial entity) at a teaching hospital in Sydney, Australia, randomly assigned 85 women with menopausal symptoms suggestive of GSM to laser (n = 43) or sham (n = 42) treatment. Participants underwent 3 treatments at monthly intervals. Laser treatments were performed with standard settings (40-watt power), while sham treatments were conducted with low settings that have no tissue effect. Local anesthesia cream was employed for all procedures, and a plume evacuator was used to remove visual and olfactory effects from laser smoke.

To maintain blinding, different clinicians performed assessments and treatments. Symptom severity assessments were based on a visual analog scale (VAS) and the Vulvovaginal Symptom Questionnaire (VSQ), with a minimal clinically important difference specified as a 50% decrease in severity scores of both assessment tools. Change in severity of symptoms, including dyspareunia, dysuria, vaginal dryness, and burning and itching, was assessed at 12 months. Quality of life, the Vaginal Health Index (VHI) score, and vaginal histology were among the secondary outcomes. In addition, vaginal biopsies were performed at baseline and 6 months after study treatment.

Among the 78 women (91.7%) who completed the 12-month evaluations, the mean age was approximately 57, more than 95% were White, and approximately half were sexually active.

Results. For the laser and sham treatment groups, at 12 months no significant differences were noted for change in overall symptoms or in the most severe symptom. Many participants who received laser or sham treatment reported an improvement in vaginal symptoms 12 months following treatment.

The VAS score for a change in symptom severity in the laser-treated group compared with the sham-treated group was -17.2 versus -26.6, a difference of 9.4 (95% confidence interval [CI], -28.6 to 47.5), while the VAS score for the most severe symptom was -24.5 versus -20.4, a difference of -4.1 (95% CI, -32.5 to 24.3). The VSQ score was, respectively, -3.1 versus -1.6 (difference, -1.5 [95% CI, -5.9 to 3.0]). The mean quality of life score showed no significant differences between the laser and the sham group (6.3 vs 1.4, a difference of 4.8 [95% CI, -3.9 to 13.5]). The VHI score was 0.9 in the laser group versus 1.3 in the sham group, for a difference of -0.4 (95% CI, -4.3 to 3.6). Likewise, the proportion of participants who noted a reduction of more than 50% in bother from their most severe symptoms was similar in the 2 groups. Similarly, changes in vaginal histology were similar in the laser and sham groups.

The proportion of participants who reported adverse events, including transient vaginal discomfort, discharge, or urinary tract symptoms, was similar in the 2 groups.

Study strengths and limitations

Although other randomized studies of fractionated laser therapy for GSM have been reported, this Australian trial is the largest and longest to date and also is the first to have used sham-treated controls.

Breast cancer survivors represent a group of patients for whom treatment of GSM can be a major conundrum—induced menopause that often results when combination chemotherapy is employed in premenopausal survivors can result in severe GSM; use of aromatase inhibitors likewise can cause bothersome GSM symptoms. Since the US Food and Drug Administration lists a personal history of breast cancer as a contraindication to use of any estrogen formulation, breast cancer survivors represent a population targeted by physicians offering vaginal laser treatment. Accordingly, that approximately 50% of trial participants were breast cancer survivors means the investigators were assessing the impact of laser therapy in a population of particular clinical relevance. Of note, as with participants overall, laser therapy when employed in breast cancer survivors did not result in outcomes distinct from sham treatments.² ●

In the longest study of bone loss in postmenopausal women to date, on average, bone mineral density (BMD) at the femoral neck (the most common location for a hip fracture) had dropped by 10% in 25 years – less than expected based on shorter studies.

Specifically, average BMD loss at the femoral neck was 0.4% per year during 25 years in this new study from Finland, compared with a drop of 1.6% per year over 15 years reported in other cohorts.

Five-year BMD change appeared to predict long-term bone loss. However, certain women had faster bone loss, indicating that they should be followed more closely.

“Although the average bone loss was 10.1% ... there is a significant variation in the bone loss rate” among women in the study, senior author Joonas Sirola, MD, PhD, associate professor, University of Eastern Finland, and coauthor Heikki Kröger, MD, PhD, a professor at the same university, explained to this news organization in an email, so “women with fast bone loss should receive special attention.

The findings from the Kuopio Osteoporosis Risk Factor and Prevention study by Anna Moilanen and colleagues were published online October 19 in the Journal of Bone and Mineral Research.

Several factors might explain the lower than expected drop in femoral neck BMD (the site that is used to diagnose osteoporosis), Dr. Sirola and Dr. Kröger said. BMD depends on a person’s age, race, sex, and genes. And compared with other countries, people in Finland consume more dairy products, and more postmenopausal women there take hormone replacement therapy (HRT).

“If otherwise indicated, HRT seemed to effectively protect from bone loss,” the researchers noted.

Also, the number of women who smoked or used corticosteroids was low, so bone loss in other populations may be higher. Moreover, the women who completed the study may have been healthier to start with, so the results should be interpreted with caution, they urge.

Nevertheless, the study sheds light on long-term changes in BMD in postmenopausal women and “stresses the importance of high peak bone mass before menopause and keeping a healthy weight” during aging to protect bone health, they say.

Indeed the work “changes our understanding of bone loss in older women,” said Dr. Kröger in a press release from the university.
 

Check BMD every 5 years after menopause

Invited to comment, American Society of Bone and Mineral Research President Peter R. Ebeling, MD, who was not involved with the research, noted key findings are that the rate of femoral neck bone loss after perimenopause was far less than previously expected, and 5-year BMD change appeared to predict long-term bone loss in postmenopausal women.

“We know bone loss begins 1 year before menopause and accelerates over the next 5 years,” Dr. Ebeling, from Monash University, Melbourne, added in an email. “This study indicates some stabilization of bone loss thereafter with lesser effects of low estrogen levels on bone.”

“It probably means bone density does not need to be measured as frequently following the menopause transition and could be every 5 years, rather than every 2 years, if there was concern about continuing bone loss.”
 

Baseline risk factors and long-term changes in BMD

For the study, researchers examined the association between risk factors for bone loss and long-term changes in femoral neck BMD in 2,695 women living in Kuopio who were 47 to 56 years old in 1989. The women were a mean age of 53 years, and 62% were postmenopausal.

They answered questionnaires and had femoral neck BMD measured by DEXA every 5 years.

A total of 2,695, 2,583, 2,482, 2,135, 1,305, and 686 women were assessed at baseline and 5-, 10-, 15-, 20- and 25-year follow-ups, respectively, indicating significant study drop-out by 25 years. 

By then, 17% of patients had died, 9% needed long-term care, some were unwilling to continue in the study, and others had factors that would have resulted in DEXA measurement errors (for example, hip implants, spine degeneration).

Researchers divided participants into quartiles of mean initial femoral neck BMD: 1.09 g/cm2, 0.97 g/cm2, 0.89 g/cm2, and 0.79 g/cm2, corresponding with quartiles 1 to 4 respectively (where quartile 1 had the highest initial femoral BMD and quartile 4 the lowest).

At 25 years, the mean femoral BMD had dropped to 0.97 g/cm2, 0.87 g/cm2, 0.80 g/cm2, and 0.73 g/cm2 in these respective quartiles.

Women lost 0.9%, 0.5%, 3.0%, and 1.0% of their initial BMD each year in quartiles 1 to 4, respectively.

And at 25 years, the women had lost 22.5%, 12.5%, 7.5%, and 2.5% of their initial BMD in the four quartiles, respectively.

Women in quartile 1 had the greatest drop in femoral BMD at 25 years, although their mean BMD at 25 years was higher than the mean initial BMD of the other women. 

The prevalence of bone-affecting diseases, smoking, and use of vitamin D/calcium supplementation, corticosteroids, or alcohol was similar in the four quartiles and was not associated with significant differences in annual bone loss.
 

The most important protective factor was HRT

However, body mass index (BMI) and HRT were significantly different in the four quartiles.

On average, women in quartile 1 had a mean BMI of 26.7 kg/m2 at baseline and 27.8 kg/m2 at 25 years. Women in quartile 4 (lowest initial BMD and lowest drop in BMD) had a mean BMI of 24.9 kg/m2 at baseline and 28.4 kg/m2 at 25 years.

Women in quartile 4 (lowest initial BMD and lowest drop in BMD) were more likely to take HRT than women in quartile 1 (highest initial BMD and highest drop in BMD), at 41% versus 26%, respectively.

“The average decrease in bone mineral density was lower than has been assumed on the basis of earlier, shorter follow-ups where the bone loss rate at the femoral neck has been estimated to be even more than 20%,” Dr. Sirola commented in the press release.

“There were also surprisingly few risk factors affecting bone mineral density. The most significant factor protecting against bone loss was hormone replacement therapy. Weight gain during the follow-up also protected against bone loss,” Dr. Sirola added.

The study was funded by the Academy of Finland, Finnish Ministry of Education and Culture, and the Päivikki and Sakari Sohlberg Foundation. The authors and Dr. Ebeling have reported no relevant financial relationships.

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

In the longest study of bone loss in postmenopausal women to date, on average, bone mineral density (BMD) at the femoral neck (the most common location for a hip fracture) had dropped by 10% in 25 years – less than expected based on shorter studies.

Specifically, average BMD loss at the femoral neck was 0.4% per year during 25 years in this new study from Finland, compared with a drop of 1.6% per year over 15 years reported in other cohorts.

Five-year BMD change appeared to predict long-term bone loss. However, certain women had faster bone loss, indicating that they should be followed more closely.

“Although the average bone loss was 10.1% ... there is a significant variation in the bone loss rate” among women in the study, senior author Joonas Sirola, MD, PhD, associate professor, University of Eastern Finland, and coauthor Heikki Kröger, MD, PhD, a professor at the same university, explained to this news organization in an email, so “women with fast bone loss should receive special attention.

The findings from the Kuopio Osteoporosis Risk Factor and Prevention study by Anna Moilanen and colleagues were published online October 19 in the Journal of Bone and Mineral Research.

Several factors might explain the lower than expected drop in femoral neck BMD (the site that is used to diagnose osteoporosis), Dr. Sirola and Dr. Kröger said. BMD depends on a person’s age, race, sex, and genes. And compared with other countries, people in Finland consume more dairy products, and more postmenopausal women there take hormone replacement therapy (HRT).

“If otherwise indicated, HRT seemed to effectively protect from bone loss,” the researchers noted.

Also, the number of women who smoked or used corticosteroids was low, so bone loss in other populations may be higher. Moreover, the women who completed the study may have been healthier to start with, so the results should be interpreted with caution, they urge.

Nevertheless, the study sheds light on long-term changes in BMD in postmenopausal women and “stresses the importance of high peak bone mass before menopause and keeping a healthy weight” during aging to protect bone health, they say.

Indeed the work “changes our understanding of bone loss in older women,” said Dr. Kröger in a press release from the university.
 

Check BMD every 5 years after menopause

Invited to comment, American Society of Bone and Mineral Research President Peter R. Ebeling, MD, who was not involved with the research, noted key findings are that the rate of femoral neck bone loss after perimenopause was far less than previously expected, and 5-year BMD change appeared to predict long-term bone loss in postmenopausal women.

“We know bone loss begins 1 year before menopause and accelerates over the next 5 years,” Dr. Ebeling, from Monash University, Melbourne, added in an email. “This study indicates some stabilization of bone loss thereafter with lesser effects of low estrogen levels on bone.”

“It probably means bone density does not need to be measured as frequently following the menopause transition and could be every 5 years, rather than every 2 years, if there was concern about continuing bone loss.”
 

Baseline risk factors and long-term changes in BMD

For the study, researchers examined the association between risk factors for bone loss and long-term changes in femoral neck BMD in 2,695 women living in Kuopio who were 47 to 56 years old in 1989. The women were a mean age of 53 years, and 62% were postmenopausal.

They answered questionnaires and had femoral neck BMD measured by DEXA every 5 years.

A total of 2,695, 2,583, 2,482, 2,135, 1,305, and 686 women were assessed at baseline and 5-, 10-, 15-, 20- and 25-year follow-ups, respectively, indicating significant study drop-out by 25 years. 

By then, 17% of patients had died, 9% needed long-term care, some were unwilling to continue in the study, and others had factors that would have resulted in DEXA measurement errors (for example, hip implants, spine degeneration).

Researchers divided participants into quartiles of mean initial femoral neck BMD: 1.09 g/cm2, 0.97 g/cm2, 0.89 g/cm2, and 0.79 g/cm2, corresponding with quartiles 1 to 4 respectively (where quartile 1 had the highest initial femoral BMD and quartile 4 the lowest).

At 25 years, the mean femoral BMD had dropped to 0.97 g/cm2, 0.87 g/cm2, 0.80 g/cm2, and 0.73 g/cm2 in these respective quartiles.

Women lost 0.9%, 0.5%, 3.0%, and 1.0% of their initial BMD each year in quartiles 1 to 4, respectively.

And at 25 years, the women had lost 22.5%, 12.5%, 7.5%, and 2.5% of their initial BMD in the four quartiles, respectively.

Women in quartile 1 had the greatest drop in femoral BMD at 25 years, although their mean BMD at 25 years was higher than the mean initial BMD of the other women. 

The prevalence of bone-affecting diseases, smoking, and use of vitamin D/calcium supplementation, corticosteroids, or alcohol was similar in the four quartiles and was not associated with significant differences in annual bone loss.
 

The most important protective factor was HRT

However, body mass index (BMI) and HRT were significantly different in the four quartiles.

On average, women in quartile 1 had a mean BMI of 26.7 kg/m2 at baseline and 27.8 kg/m2 at 25 years. Women in quartile 4 (lowest initial BMD and lowest drop in BMD) had a mean BMI of 24.9 kg/m2 at baseline and 28.4 kg/m2 at 25 years.

Women in quartile 4 (lowest initial BMD and lowest drop in BMD) were more likely to take HRT than women in quartile 1 (highest initial BMD and highest drop in BMD), at 41% versus 26%, respectively.

“The average decrease in bone mineral density was lower than has been assumed on the basis of earlier, shorter follow-ups where the bone loss rate at the femoral neck has been estimated to be even more than 20%,” Dr. Sirola commented in the press release.

“There were also surprisingly few risk factors affecting bone mineral density. The most significant factor protecting against bone loss was hormone replacement therapy. Weight gain during the follow-up also protected against bone loss,” Dr. Sirola added.

The study was funded by the Academy of Finland, Finnish Ministry of Education and Culture, and the Päivikki and Sakari Sohlberg Foundation. The authors and Dr. Ebeling have reported no relevant financial relationships.

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

In the longest study of bone loss in postmenopausal women to date, on average, bone mineral density (BMD) at the femoral neck (the most common location for a hip fracture) had dropped by 10% in 25 years – less than expected based on shorter studies.

Specifically, average BMD loss at the femoral neck was 0.4% per year during 25 years in this new study from Finland, compared with a drop of 1.6% per year over 15 years reported in other cohorts.

Five-year BMD change appeared to predict long-term bone loss. However, certain women had faster bone loss, indicating that they should be followed more closely.

“Although the average bone loss was 10.1% ... there is a significant variation in the bone loss rate” among women in the study, senior author Joonas Sirola, MD, PhD, associate professor, University of Eastern Finland, and coauthor Heikki Kröger, MD, PhD, a professor at the same university, explained to this news organization in an email, so “women with fast bone loss should receive special attention.

The findings from the Kuopio Osteoporosis Risk Factor and Prevention study by Anna Moilanen and colleagues were published online October 19 in the Journal of Bone and Mineral Research.

Several factors might explain the lower than expected drop in femoral neck BMD (the site that is used to diagnose osteoporosis), Dr. Sirola and Dr. Kröger said. BMD depends on a person’s age, race, sex, and genes. And compared with other countries, people in Finland consume more dairy products, and more postmenopausal women there take hormone replacement therapy (HRT).

“If otherwise indicated, HRT seemed to effectively protect from bone loss,” the researchers noted.

Also, the number of women who smoked or used corticosteroids was low, so bone loss in other populations may be higher. Moreover, the women who completed the study may have been healthier to start with, so the results should be interpreted with caution, they urge.

Nevertheless, the study sheds light on long-term changes in BMD in postmenopausal women and “stresses the importance of high peak bone mass before menopause and keeping a healthy weight” during aging to protect bone health, they say.

Indeed the work “changes our understanding of bone loss in older women,” said Dr. Kröger in a press release from the university.
 

Check BMD every 5 years after menopause

Invited to comment, American Society of Bone and Mineral Research President Peter R. Ebeling, MD, who was not involved with the research, noted key findings are that the rate of femoral neck bone loss after perimenopause was far less than previously expected, and 5-year BMD change appeared to predict long-term bone loss in postmenopausal women.

“We know bone loss begins 1 year before menopause and accelerates over the next 5 years,” Dr. Ebeling, from Monash University, Melbourne, added in an email. “This study indicates some stabilization of bone loss thereafter with lesser effects of low estrogen levels on bone.”

“It probably means bone density does not need to be measured as frequently following the menopause transition and could be every 5 years, rather than every 2 years, if there was concern about continuing bone loss.”
 

Baseline risk factors and long-term changes in BMD

For the study, researchers examined the association between risk factors for bone loss and long-term changes in femoral neck BMD in 2,695 women living in Kuopio who were 47 to 56 years old in 1989. The women were a mean age of 53 years, and 62% were postmenopausal.

They answered questionnaires and had femoral neck BMD measured by DEXA every 5 years.

A total of 2,695, 2,583, 2,482, 2,135, 1,305, and 686 women were assessed at baseline and 5-, 10-, 15-, 20- and 25-year follow-ups, respectively, indicating significant study drop-out by 25 years. 

By then, 17% of patients had died, 9% needed long-term care, some were unwilling to continue in the study, and others had factors that would have resulted in DEXA measurement errors (for example, hip implants, spine degeneration).

Researchers divided participants into quartiles of mean initial femoral neck BMD: 1.09 g/cm2, 0.97 g/cm2, 0.89 g/cm2, and 0.79 g/cm2, corresponding with quartiles 1 to 4 respectively (where quartile 1 had the highest initial femoral BMD and quartile 4 the lowest).

At 25 years, the mean femoral BMD had dropped to 0.97 g/cm2, 0.87 g/cm2, 0.80 g/cm2, and 0.73 g/cm2 in these respective quartiles.

Women lost 0.9%, 0.5%, 3.0%, and 1.0% of their initial BMD each year in quartiles 1 to 4, respectively.

And at 25 years, the women had lost 22.5%, 12.5%, 7.5%, and 2.5% of their initial BMD in the four quartiles, respectively.

Women in quartile 1 had the greatest drop in femoral BMD at 25 years, although their mean BMD at 25 years was higher than the mean initial BMD of the other women. 

The prevalence of bone-affecting diseases, smoking, and use of vitamin D/calcium supplementation, corticosteroids, or alcohol was similar in the four quartiles and was not associated with significant differences in annual bone loss.
 

The most important protective factor was HRT

However, body mass index (BMI) and HRT were significantly different in the four quartiles.

On average, women in quartile 1 had a mean BMI of 26.7 kg/m2 at baseline and 27.8 kg/m2 at 25 years. Women in quartile 4 (lowest initial BMD and lowest drop in BMD) had a mean BMI of 24.9 kg/m2 at baseline and 28.4 kg/m2 at 25 years.

Women in quartile 4 (lowest initial BMD and lowest drop in BMD) were more likely to take HRT than women in quartile 1 (highest initial BMD and highest drop in BMD), at 41% versus 26%, respectively.

“The average decrease in bone mineral density was lower than has been assumed on the basis of earlier, shorter follow-ups where the bone loss rate at the femoral neck has been estimated to be even more than 20%,” Dr. Sirola commented in the press release.

“There were also surprisingly few risk factors affecting bone mineral density. The most significant factor protecting against bone loss was hormone replacement therapy. Weight gain during the follow-up also protected against bone loss,” Dr. Sirola added.

The study was funded by the Academy of Finland, Finnish Ministry of Education and Culture, and the Päivikki and Sakari Sohlberg Foundation. The authors and Dr. Ebeling have reported no relevant financial relationships.

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

Although early menopause is linked to increased risks in bone loss and fracture, new research indicates that, even among the majority of women who have menopause after age 45, the time since the final menstrual period can be a stronger predictor than chronological age for key risks in bone health and fracture.

Steve Debenport/Getty Images

In a large longitudinal cohort, the number of years since a woman’s final menstrual period specifically showed a stronger association with femoral neck bone mineral density (BMD) than chronological age, while an earlier age at menopause – even among those over 45 years, was linked to an increased risk of fracture.

“Most of our clinical tools to predict osteoporosis-related outcomes use chronological age,” first author Albert Shieh, MD, told this news organization.

“Our findings suggest that more research should be done to examine whether ovarian age (time since final menstrual period) should be used in these tools as well.”

An increased focus on the significance of age at the time of the final menstrual period, compared with chronological age, has gained interest in risk assessment because of the known acceleration in the decline of BMD that occurs 1 year prior to the final menstrual period and continues at a rapid pace for 3 years afterwards before slowing.

To further investigate the association with BMD, Dr. Shieh, an endocrinologist specializing in osteoporosis at the University of California, Los Angeles, and his colleagues turned to data from the Study of Women’s Health Across the Nation (SWAN), a longitudinal cohort study of ambulatory women with pre- or early perimenopausal baseline data and 15 annual follow-up assessments.

Outcomes regarding postmenopausal lumbar spine (LS) or femoral neck (FN) BMD were evaluated in 1,038 women, while the time to fracture in relation to the final menstrual period was separately evaluated in 1,554 women.

In both cohorts, the women had a known final menstrual period at age 45 or older, and on average, their final menstrual period occurred at age 52.

After a multivariate adjustment for age, body mass index, and various other factors, they found that each additional year after a woman’s final menstrual period was associated with a significant (0.006 g/cm²) reduction in postmenopausal lumbar spine BMD and a 0.004 g/cm² reduction femoral neck BMD (both P < .0001).

Conversely, chronological age was not associated with a change in femoral neck BMD when evaluated independently of years since the final menstrual period, the researchers reported in the Journal of Clinical Endocrinology and Metabolism.

Regarding lumbar spine BMD, chronological age was unexpectedly associated not just with change, but in fact with increases in lumbar spine BMD (P < .0001 per year). However, the authors speculate the change “is likely a reflection of age-associated degenerative changes causing false elevations in BMD measured by dual-energy x-ray absorptiometry.”

Fracture risk with earlier menopause

In terms of the fracture risk analysis, despite the women all being aged 45 or older, earlier age at menopause was still tied to an increased risk of incident fracture, with a 5% increase in risk for each earlier year in age at the time of the final menstrual period (P = .02).

Compared with women who had their final menstrual period at age 55, for instance, those who finished menstruating at age 47 had a 6.3% greater 20-year cumulative fracture risk, the authors note.

While previous findings from the Malmo Perimenopausal Study showed menopause prior to the age of 47 to be associated with an 83% and 59% greater risk of densitometric osteoporosis and fracture, respectively, by age 77, the authors note that the new study is unique in including only women who had a final menstrual period over the age of 45, therefore reducing the potential confounding of data on women under 45.

The new results “add to a growing body of literature suggesting that the endocrine changes that occur during the menopause transition trigger a pathophysiologic cascade that leads to organ dysfunction,” the authors note.

In terms of implications in risk assessment, “future studies should examine whether years since the final menstrual period predicts major osteoporotic fractures and hip fractures, specifically, and, if so, whether replacing chronological age with years since the final menstrual period improves the performance of clinical prediction tools, such as FRAX [Fracture Risk Assessment Tool],” they add.

Addition to guidelines?

Commenting on the findings, Peter Ebeling, MD, the current president of the American Society of Bone and Mineral Research, noted that the study importantly “confirms what we had previously anticipated, that in women with menopause who are 45 years of age or older a lower age of final menstrual period is associated with lower spine and hip BMD and more fractures.”

“We had already known this for women with premature ovarian insufficiency or an early menopause, and this extends the observation to the vast majority of women – more than 90% – with a normal menopause age,” said Dr. Ebeling, professor of medicine at Monash Health, Monash University, in Melbourne.

Despite the known importance of the time since final menstrual period, guidelines still focus on age in terms of chronology, rather than biology, emphasizing the risk among women over 50, in general, rather than the time since the last menstrual period, he noted.

“There is an important difference [between those two], as shown by this study,” he said. “Guidelines could be easily adapted to reflect this.”

Specifically, the association between lower age of final menstrual period and lower spine and hip BMD and more fractures requires “more formal assessment to determine whether adding age of final menstrual period to existing fracture risk calculator tools, like FRAX, can improve absolute fracture risk prediction,” Dr. Ebeling noted.

The authors and Dr. Ebeling had no disclosures to report.

Although early menopause is linked to increased risks in bone loss and fracture, new research indicates that, even among the majority of women who have menopause after age 45, the time since the final menstrual period can be a stronger predictor than chronological age for key risks in bone health and fracture.

Steve Debenport/Getty Images

In a large longitudinal cohort, the number of years since a woman’s final menstrual period specifically showed a stronger association with femoral neck bone mineral density (BMD) than chronological age, while an earlier age at menopause – even among those over 45 years, was linked to an increased risk of fracture.

“Most of our clinical tools to predict osteoporosis-related outcomes use chronological age,” first author Albert Shieh, MD, told this news organization.

“Our findings suggest that more research should be done to examine whether ovarian age (time since final menstrual period) should be used in these tools as well.”

An increased focus on the significance of age at the time of the final menstrual period, compared with chronological age, has gained interest in risk assessment because of the known acceleration in the decline of BMD that occurs 1 year prior to the final menstrual period and continues at a rapid pace for 3 years afterwards before slowing.

To further investigate the association with BMD, Dr. Shieh, an endocrinologist specializing in osteoporosis at the University of California, Los Angeles, and his colleagues turned to data from the Study of Women’s Health Across the Nation (SWAN), a longitudinal cohort study of ambulatory women with pre- or early perimenopausal baseline data and 15 annual follow-up assessments.

Outcomes regarding postmenopausal lumbar spine (LS) or femoral neck (FN) BMD were evaluated in 1,038 women, while the time to fracture in relation to the final menstrual period was separately evaluated in 1,554 women.

In both cohorts, the women had a known final menstrual period at age 45 or older, and on average, their final menstrual period occurred at age 52.

After a multivariate adjustment for age, body mass index, and various other factors, they found that each additional year after a woman’s final menstrual period was associated with a significant (0.006 g/cm²) reduction in postmenopausal lumbar spine BMD and a 0.004 g/cm² reduction femoral neck BMD (both P < .0001).

Conversely, chronological age was not associated with a change in femoral neck BMD when evaluated independently of years since the final menstrual period, the researchers reported in the Journal of Clinical Endocrinology and Metabolism.

Regarding lumbar spine BMD, chronological age was unexpectedly associated not just with change, but in fact with increases in lumbar spine BMD (P < .0001 per year). However, the authors speculate the change “is likely a reflection of age-associated degenerative changes causing false elevations in BMD measured by dual-energy x-ray absorptiometry.”

Fracture risk with earlier menopause

In terms of the fracture risk analysis, despite the women all being aged 45 or older, earlier age at menopause was still tied to an increased risk of incident fracture, with a 5% increase in risk for each earlier year in age at the time of the final menstrual period (P = .02).

Compared with women who had their final menstrual period at age 55, for instance, those who finished menstruating at age 47 had a 6.3% greater 20-year cumulative fracture risk, the authors note.

While previous findings from the Malmo Perimenopausal Study showed menopause prior to the age of 47 to be associated with an 83% and 59% greater risk of densitometric osteoporosis and fracture, respectively, by age 77, the authors note that the new study is unique in including only women who had a final menstrual period over the age of 45, therefore reducing the potential confounding of data on women under 45.

The new results “add to a growing body of literature suggesting that the endocrine changes that occur during the menopause transition trigger a pathophysiologic cascade that leads to organ dysfunction,” the authors note.

In terms of implications in risk assessment, “future studies should examine whether years since the final menstrual period predicts major osteoporotic fractures and hip fractures, specifically, and, if so, whether replacing chronological age with years since the final menstrual period improves the performance of clinical prediction tools, such as FRAX [Fracture Risk Assessment Tool],” they add.

Addition to guidelines?

Commenting on the findings, Peter Ebeling, MD, the current president of the American Society of Bone and Mineral Research, noted that the study importantly “confirms what we had previously anticipated, that in women with menopause who are 45 years of age or older a lower age of final menstrual period is associated with lower spine and hip BMD and more fractures.”

“We had already known this for women with premature ovarian insufficiency or an early menopause, and this extends the observation to the vast majority of women – more than 90% – with a normal menopause age,” said Dr. Ebeling, professor of medicine at Monash Health, Monash University, in Melbourne.

Despite the known importance of the time since final menstrual period, guidelines still focus on age in terms of chronology, rather than biology, emphasizing the risk among women over 50, in general, rather than the time since the last menstrual period, he noted.

“There is an important difference [between those two], as shown by this study,” he said. “Guidelines could be easily adapted to reflect this.”

Specifically, the association between lower age of final menstrual period and lower spine and hip BMD and more fractures requires “more formal assessment to determine whether adding age of final menstrual period to existing fracture risk calculator tools, like FRAX, can improve absolute fracture risk prediction,” Dr. Ebeling noted.

The authors and Dr. Ebeling had no disclosures to report.

Although early menopause is linked to increased risks in bone loss and fracture, new research indicates that, even among the majority of women who have menopause after age 45, the time since the final menstrual period can be a stronger predictor than chronological age for key risks in bone health and fracture.

Steve Debenport/Getty Images

In a large longitudinal cohort, the number of years since a woman’s final menstrual period specifically showed a stronger association with femoral neck bone mineral density (BMD) than chronological age, while an earlier age at menopause – even among those over 45 years, was linked to an increased risk of fracture.

“Most of our clinical tools to predict osteoporosis-related outcomes use chronological age,” first author Albert Shieh, MD, told this news organization.

“Our findings suggest that more research should be done to examine whether ovarian age (time since final menstrual period) should be used in these tools as well.”

An increased focus on the significance of age at the time of the final menstrual period, compared with chronological age, has gained interest in risk assessment because of the known acceleration in the decline of BMD that occurs 1 year prior to the final menstrual period and continues at a rapid pace for 3 years afterwards before slowing.

To further investigate the association with BMD, Dr. Shieh, an endocrinologist specializing in osteoporosis at the University of California, Los Angeles, and his colleagues turned to data from the Study of Women’s Health Across the Nation (SWAN), a longitudinal cohort study of ambulatory women with pre- or early perimenopausal baseline data and 15 annual follow-up assessments.

Outcomes regarding postmenopausal lumbar spine (LS) or femoral neck (FN) BMD were evaluated in 1,038 women, while the time to fracture in relation to the final menstrual period was separately evaluated in 1,554 women.

In both cohorts, the women had a known final menstrual period at age 45 or older, and on average, their final menstrual period occurred at age 52.

After a multivariate adjustment for age, body mass index, and various other factors, they found that each additional year after a woman’s final menstrual period was associated with a significant (0.006 g/cm²) reduction in postmenopausal lumbar spine BMD and a 0.004 g/cm² reduction femoral neck BMD (both P < .0001).

Conversely, chronological age was not associated with a change in femoral neck BMD when evaluated independently of years since the final menstrual period, the researchers reported in the Journal of Clinical Endocrinology and Metabolism.

Regarding lumbar spine BMD, chronological age was unexpectedly associated not just with change, but in fact with increases in lumbar spine BMD (P < .0001 per year). However, the authors speculate the change “is likely a reflection of age-associated degenerative changes causing false elevations in BMD measured by dual-energy x-ray absorptiometry.”

Fracture risk with earlier menopause

In terms of the fracture risk analysis, despite the women all being aged 45 or older, earlier age at menopause was still tied to an increased risk of incident fracture, with a 5% increase in risk for each earlier year in age at the time of the final menstrual period (P = .02).

Compared with women who had their final menstrual period at age 55, for instance, those who finished menstruating at age 47 had a 6.3% greater 20-year cumulative fracture risk, the authors note.

While previous findings from the Malmo Perimenopausal Study showed menopause prior to the age of 47 to be associated with an 83% and 59% greater risk of densitometric osteoporosis and fracture, respectively, by age 77, the authors note that the new study is unique in including only women who had a final menstrual period over the age of 45, therefore reducing the potential confounding of data on women under 45.

The new results “add to a growing body of literature suggesting that the endocrine changes that occur during the menopause transition trigger a pathophysiologic cascade that leads to organ dysfunction,” the authors note.

In terms of implications in risk assessment, “future studies should examine whether years since the final menstrual period predicts major osteoporotic fractures and hip fractures, specifically, and, if so, whether replacing chronological age with years since the final menstrual period improves the performance of clinical prediction tools, such as FRAX [Fracture Risk Assessment Tool],” they add.

Addition to guidelines?

Commenting on the findings, Peter Ebeling, MD, the current president of the American Society of Bone and Mineral Research, noted that the study importantly “confirms what we had previously anticipated, that in women with menopause who are 45 years of age or older a lower age of final menstrual period is associated with lower spine and hip BMD and more fractures.”

“We had already known this for women with premature ovarian insufficiency or an early menopause, and this extends the observation to the vast majority of women – more than 90% – with a normal menopause age,” said Dr. Ebeling, professor of medicine at Monash Health, Monash University, in Melbourne.

Despite the known importance of the time since final menstrual period, guidelines still focus on age in terms of chronology, rather than biology, emphasizing the risk among women over 50, in general, rather than the time since the last menstrual period, he noted.

“There is an important difference [between those two], as shown by this study,” he said. “Guidelines could be easily adapted to reflect this.”

Specifically, the association between lower age of final menstrual period and lower spine and hip BMD and more fractures requires “more formal assessment to determine whether adding age of final menstrual period to existing fracture risk calculator tools, like FRAX, can improve absolute fracture risk prediction,” Dr. Ebeling noted.

The authors and Dr. Ebeling had no disclosures to report.

Women who had a preterm delivery were at least 1.6 times as likely to develop hypertension over the next decade as those who had full-term deliveries, based on data from a national cohort study of more than 2 million women.

Pregnancy complications such as preeclampsia and other hypertensive disorders of pregnancy have been associated with chronic hypertension as well as with preterm delivery, but the independent role of preterm delivery in chronic hypertension risk remains unclear, Casey Crump, MD, of the Icahn School of Medicine at Mount Sinai, New York, and colleagues wrote. “A better understanding of the long-term hypertension risks associated with preterm delivery is needed to improve risk stratification, clinical monitoring, and CVD [cardiovascular disease] prevention in women.”

In a study published in JAMA Cardiology, the researchers reviewed data from 2,195,989 women with 4,308,286 singleton deliveries in Sweden from Jan. 1, 1973, to Dec. 31, 2015. Women with preexisting hypertension before their first pregnancy were excluded. Pregnancy duration was based on maternal reports of the last menstrual period for patients in the 1970s, and based on ultrasound estimates in the 1980s and beyond. Pregnancy duration was divided into six groups in terms of completed weeks of gestation: extremely preterm (22-27 weeks), moderately preterm (28-33 weeks), late preterm (34-36 weeks), early term (37-38 weeks), full term (39-41 weeks), and post term (≥42 weeks). Full-term delivery was used as the reference, and the three preterm groups were combined for summaries of preterm delivery (less than 37 weeks).

Overall, women who delivered at less than 37 weeks’ gestation had a 1.6-fold increased risk of hypertension (adjusted hazard ratio, 1.67) within the next 10 years, compared with women who delivered full term after controlling for preeclampsia, other hypertensive disorders of pregnancy, and maternal factors.

When further stratified by pregnancy duration, the aHRs for extremely preterm, moderately preterm, late preterm, and early term, compared with full-term deliveries were 2.23, 1.85, 1.55, and 1.26, respectively, in the first decade after delivery. Each additional week of pregnancy was associated with a mean 7% reduction in hypertension risk (a HR, 0.93).

The increased hypertension risk following preterm delivery (less than 37 weeks) persisted at 10-19 years, 20-29 years, and 30-43 years, with aHRs of 1.40, 1.20, and 1.12, respectively. Early-term delivery at 37-38 weeks also carried an increased risk of long-term hypertension compared with full-term delivery, with aHRs of 1.12 and 1.06 at 20-29 years and 30-43 years, respectively.

“Cosibling analyses suggested that these findings were only partially explained by familial (genetic and/or early-life environmental) factors that are shared determinants of both preterm delivery and hypertension,” the researchers noted. The findings suggest that preterm delivery itself may contribute to or affect the pathophysiology that leads to cardiovascular disease, they added, hypothesizing that endothelial dysfunction caused by preterm delivery may cause functional impairments in the microvasculature.

The study findings were limited by several factors including the lack of detailed records to verify hypertension and the use of data from a single country, the researchers noted. However, the results were strengthened by the large study population, the use of highly complete prenatal and birth records to minimize selection bias, and the long-term follow-up.

The results are consistent with those from previous studies, and support the recognition of preterm delivery as a lifetime risk factor for hypertension, but future studies should focus on racial and ethnic subgroups already at increased risk for both preterm delivery and hypertension, they added.

“Additional follow-up will be needed to examine these associations in older adulthood when hypertension increasingly and disproportionately affects women,” they concluded.

Data highlight the need for patient and provider education

“This study furthers our knowledge regarding long-term complications associated with the frequent pregnancy complication of preterm delivery,” Stephen S. Crane, MD, an ob.gyn. and maternal-fetal medicine specialist in private practice in Orlando, said in an interview. “Cardiovascular disease is the leading cause of death and often goes unrecognized in women. There are shared risk factors among women and men for developing CVD, the most common being hypertension. However, women have the unique risk factor of pregnancy and its attendant complications including preeclampsia, glucose intolerance, and preterm delivery. Hypertensive disorders in pregnancy often lead to indicated premature delivery, and are associated with development of chronic hypertension and subsequent CVD. However, prior data suggest that preterm delivery itself is a risk factor for developing chronic hypertension later in life.

“The current study, which evaluates one of the most complete population data sets with up to 43 years of follow-up, is the first to assess for familial determinants by cosibling analysis, and supports preterm delivery as an independent risk factor for the development of hypertension,” he said. The study results illustrate that this risk is longstanding, and that recurrent preterm birth further increases the risk of developing hypertension.

Dr. Crane said he was not surprised by the study findings, given that inflammatory processes have been linked to the development of hypertension and CVD. “Similarly, inflammatory processes have been implicated in the pathophysiology of preterm labor and inflammatory cytokines may also play a role in normal term labor. Therefore, it is not surprising that preterm delivery would be a marker for the risk of development of hypertension, as both may be responses to underlying inflammatory processes. Identification of these underlying inflammatory processes and methods for prevention will be critical if we are to decrease both the incidence of preterm birth and CVD.

“As prenatal care may be the only medical care women obtain, it is important to take this opportunity to educate patients regarding their long-term risks of developing hypertension and the need for long-term follow up. Interventions that may help reduce the risk for recurrent preterm birth and long-term risks for developing hypertension and CVD include weight loss, increased activity, and smoking cessation; the resources to achieve these goals need to be shared with patients,” he said.

“Knowledge deficits both on the part of the provider and patient may be a significant barrier to intervention that may be overcome with improved education,” said Dr. Crane. “Care providers need education regarding the long-term risks associated with a history of preterm delivery in order to better educate their patients regarding both prevention of recurrent preterm birth and the development of hypertension and CVD.” However, socioeconomic status, education level, and the inability to obtain further health care remain common barriers to intervention for many women.

“Additional research is needed to identify the causes of inflammatory processes leading to preterm delivery and risks for hypertension and CVD,” said Dr. Crane. “Only after the causes are identified can treatments be sought to successfully treat these conditions.”

The study was supported by the National Heart, Lung, and Blood Institute at the National Institutes of Health; the Swedish Research Council; the Swedish Heart-Lung Foundation; and an Avtal om Läkarutbildning och Forskning (Agreement on Medical Training and Research) (ALF) project grant from Region Skåne/Lund University. Neither the researchers nor Dr. Crane had any financial conflicts to disclose.

Women who had a preterm delivery were at least 1.6 times as likely to develop hypertension over the next decade as those who had full-term deliveries, based on data from a national cohort study of more than 2 million women.

Pregnancy complications such as preeclampsia and other hypertensive disorders of pregnancy have been associated with chronic hypertension as well as with preterm delivery, but the independent role of preterm delivery in chronic hypertension risk remains unclear, Casey Crump, MD, of the Icahn School of Medicine at Mount Sinai, New York, and colleagues wrote. “A better understanding of the long-term hypertension risks associated with preterm delivery is needed to improve risk stratification, clinical monitoring, and CVD [cardiovascular disease] prevention in women.”

In a study published in JAMA Cardiology, the researchers reviewed data from 2,195,989 women with 4,308,286 singleton deliveries in Sweden from Jan. 1, 1973, to Dec. 31, 2015. Women with preexisting hypertension before their first pregnancy were excluded. Pregnancy duration was based on maternal reports of the last menstrual period for patients in the 1970s, and based on ultrasound estimates in the 1980s and beyond. Pregnancy duration was divided into six groups in terms of completed weeks of gestation: extremely preterm (22-27 weeks), moderately preterm (28-33 weeks), late preterm (34-36 weeks), early term (37-38 weeks), full term (39-41 weeks), and post term (≥42 weeks). Full-term delivery was used as the reference, and the three preterm groups were combined for summaries of preterm delivery (less than 37 weeks).

Overall, women who delivered at less than 37 weeks’ gestation had a 1.6-fold increased risk of hypertension (adjusted hazard ratio, 1.67) within the next 10 years, compared with women who delivered full term after controlling for preeclampsia, other hypertensive disorders of pregnancy, and maternal factors.

When further stratified by pregnancy duration, the aHRs for extremely preterm, moderately preterm, late preterm, and early term, compared with full-term deliveries were 2.23, 1.85, 1.55, and 1.26, respectively, in the first decade after delivery. Each additional week of pregnancy was associated with a mean 7% reduction in hypertension risk (a HR, 0.93).

The increased hypertension risk following preterm delivery (less than 37 weeks) persisted at 10-19 years, 20-29 years, and 30-43 years, with aHRs of 1.40, 1.20, and 1.12, respectively. Early-term delivery at 37-38 weeks also carried an increased risk of long-term hypertension compared with full-term delivery, with aHRs of 1.12 and 1.06 at 20-29 years and 30-43 years, respectively.

“Cosibling analyses suggested that these findings were only partially explained by familial (genetic and/or early-life environmental) factors that are shared determinants of both preterm delivery and hypertension,” the researchers noted. The findings suggest that preterm delivery itself may contribute to or affect the pathophysiology that leads to cardiovascular disease, they added, hypothesizing that endothelial dysfunction caused by preterm delivery may cause functional impairments in the microvasculature.

The study findings were limited by several factors including the lack of detailed records to verify hypertension and the use of data from a single country, the researchers noted. However, the results were strengthened by the large study population, the use of highly complete prenatal and birth records to minimize selection bias, and the long-term follow-up.

The results are consistent with those from previous studies, and support the recognition of preterm delivery as a lifetime risk factor for hypertension, but future studies should focus on racial and ethnic subgroups already at increased risk for both preterm delivery and hypertension, they added.

“Additional follow-up will be needed to examine these associations in older adulthood when hypertension increasingly and disproportionately affects women,” they concluded.

Data highlight the need for patient and provider education

“This study furthers our knowledge regarding long-term complications associated with the frequent pregnancy complication of preterm delivery,” Stephen S. Crane, MD, an ob.gyn. and maternal-fetal medicine specialist in private practice in Orlando, said in an interview. “Cardiovascular disease is the leading cause of death and often goes unrecognized in women. There are shared risk factors among women and men for developing CVD, the most common being hypertension. However, women have the unique risk factor of pregnancy and its attendant complications including preeclampsia, glucose intolerance, and preterm delivery. Hypertensive disorders in pregnancy often lead to indicated premature delivery, and are associated with development of chronic hypertension and subsequent CVD. However, prior data suggest that preterm delivery itself is a risk factor for developing chronic hypertension later in life.

“The current study, which evaluates one of the most complete population data sets with up to 43 years of follow-up, is the first to assess for familial determinants by cosibling analysis, and supports preterm delivery as an independent risk factor for the development of hypertension,” he said. The study results illustrate that this risk is longstanding, and that recurrent preterm birth further increases the risk of developing hypertension.

Dr. Crane said he was not surprised by the study findings, given that inflammatory processes have been linked to the development of hypertension and CVD. “Similarly, inflammatory processes have been implicated in the pathophysiology of preterm labor and inflammatory cytokines may also play a role in normal term labor. Therefore, it is not surprising that preterm delivery would be a marker for the risk of development of hypertension, as both may be responses to underlying inflammatory processes. Identification of these underlying inflammatory processes and methods for prevention will be critical if we are to decrease both the incidence of preterm birth and CVD.

“As prenatal care may be the only medical care women obtain, it is important to take this opportunity to educate patients regarding their long-term risks of developing hypertension and the need for long-term follow up. Interventions that may help reduce the risk for recurrent preterm birth and long-term risks for developing hypertension and CVD include weight loss, increased activity, and smoking cessation; the resources to achieve these goals need to be shared with patients,” he said.

“Knowledge deficits both on the part of the provider and patient may be a significant barrier to intervention that may be overcome with improved education,” said Dr. Crane. “Care providers need education regarding the long-term risks associated with a history of preterm delivery in order to better educate their patients regarding both prevention of recurrent preterm birth and the development of hypertension and CVD.” However, socioeconomic status, education level, and the inability to obtain further health care remain common barriers to intervention for many women.

“Additional research is needed to identify the causes of inflammatory processes leading to preterm delivery and risks for hypertension and CVD,” said Dr. Crane. “Only after the causes are identified can treatments be sought to successfully treat these conditions.”

The study was supported by the National Heart, Lung, and Blood Institute at the National Institutes of Health; the Swedish Research Council; the Swedish Heart-Lung Foundation; and an Avtal om Läkarutbildning och Forskning (Agreement on Medical Training and Research) (ALF) project grant from Region Skåne/Lund University. Neither the researchers nor Dr. Crane had any financial conflicts to disclose.

Women who had a preterm delivery were at least 1.6 times as likely to develop hypertension over the next decade as those who had full-term deliveries, based on data from a national cohort study of more than 2 million women.

Pregnancy complications such as preeclampsia and other hypertensive disorders of pregnancy have been associated with chronic hypertension as well as with preterm delivery, but the independent role of preterm delivery in chronic hypertension risk remains unclear, Casey Crump, MD, of the Icahn School of Medicine at Mount Sinai, New York, and colleagues wrote. “A better understanding of the long-term hypertension risks associated with preterm delivery is needed to improve risk stratification, clinical monitoring, and CVD [cardiovascular disease] prevention in women.”

In a study published in JAMA Cardiology, the researchers reviewed data from 2,195,989 women with 4,308,286 singleton deliveries in Sweden from Jan. 1, 1973, to Dec. 31, 2015. Women with preexisting hypertension before their first pregnancy were excluded. Pregnancy duration was based on maternal reports of the last menstrual period for patients in the 1970s, and based on ultrasound estimates in the 1980s and beyond. Pregnancy duration was divided into six groups in terms of completed weeks of gestation: extremely preterm (22-27 weeks), moderately preterm (28-33 weeks), late preterm (34-36 weeks), early term (37-38 weeks), full term (39-41 weeks), and post term (≥42 weeks). Full-term delivery was used as the reference, and the three preterm groups were combined for summaries of preterm delivery (less than 37 weeks).

Overall, women who delivered at less than 37 weeks’ gestation had a 1.6-fold increased risk of hypertension (adjusted hazard ratio, 1.67) within the next 10 years, compared with women who delivered full term after controlling for preeclampsia, other hypertensive disorders of pregnancy, and maternal factors.

When further stratified by pregnancy duration, the aHRs for extremely preterm, moderately preterm, late preterm, and early term, compared with full-term deliveries were 2.23, 1.85, 1.55, and 1.26, respectively, in the first decade after delivery. Each additional week of pregnancy was associated with a mean 7% reduction in hypertension risk (a HR, 0.93).

The increased hypertension risk following preterm delivery (less than 37 weeks) persisted at 10-19 years, 20-29 years, and 30-43 years, with aHRs of 1.40, 1.20, and 1.12, respectively. Early-term delivery at 37-38 weeks also carried an increased risk of long-term hypertension compared with full-term delivery, with aHRs of 1.12 and 1.06 at 20-29 years and 30-43 years, respectively.

“Cosibling analyses suggested that these findings were only partially explained by familial (genetic and/or early-life environmental) factors that are shared determinants of both preterm delivery and hypertension,” the researchers noted. The findings suggest that preterm delivery itself may contribute to or affect the pathophysiology that leads to cardiovascular disease, they added, hypothesizing that endothelial dysfunction caused by preterm delivery may cause functional impairments in the microvasculature.

The study findings were limited by several factors including the lack of detailed records to verify hypertension and the use of data from a single country, the researchers noted. However, the results were strengthened by the large study population, the use of highly complete prenatal and birth records to minimize selection bias, and the long-term follow-up.

The results are consistent with those from previous studies, and support the recognition of preterm delivery as a lifetime risk factor for hypertension, but future studies should focus on racial and ethnic subgroups already at increased risk for both preterm delivery and hypertension, they added.

“Additional follow-up will be needed to examine these associations in older adulthood when hypertension increasingly and disproportionately affects women,” they concluded.

Data highlight the need for patient and provider education

“This study furthers our knowledge regarding long-term complications associated with the frequent pregnancy complication of preterm delivery,” Stephen S. Crane, MD, an ob.gyn. and maternal-fetal medicine specialist in private practice in Orlando, said in an interview. “Cardiovascular disease is the leading cause of death and often goes unrecognized in women. There are shared risk factors among women and men for developing CVD, the most common being hypertension. However, women have the unique risk factor of pregnancy and its attendant complications including preeclampsia, glucose intolerance, and preterm delivery. Hypertensive disorders in pregnancy often lead to indicated premature delivery, and are associated with development of chronic hypertension and subsequent CVD. However, prior data suggest that preterm delivery itself is a risk factor for developing chronic hypertension later in life.

“The current study, which evaluates one of the most complete population data sets with up to 43 years of follow-up, is the first to assess for familial determinants by cosibling analysis, and supports preterm delivery as an independent risk factor for the development of hypertension,” he said. The study results illustrate that this risk is longstanding, and that recurrent preterm birth further increases the risk of developing hypertension.

Dr. Crane said he was not surprised by the study findings, given that inflammatory processes have been linked to the development of hypertension and CVD. “Similarly, inflammatory processes have been implicated in the pathophysiology of preterm labor and inflammatory cytokines may also play a role in normal term labor. Therefore, it is not surprising that preterm delivery would be a marker for the risk of development of hypertension, as both may be responses to underlying inflammatory processes. Identification of these underlying inflammatory processes and methods for prevention will be critical if we are to decrease both the incidence of preterm birth and CVD.

“As prenatal care may be the only medical care women obtain, it is important to take this opportunity to educate patients regarding their long-term risks of developing hypertension and the need for long-term follow up. Interventions that may help reduce the risk for recurrent preterm birth and long-term risks for developing hypertension and CVD include weight loss, increased activity, and smoking cessation; the resources to achieve these goals need to be shared with patients,” he said.

“Knowledge deficits both on the part of the provider and patient may be a significant barrier to intervention that may be overcome with improved education,” said Dr. Crane. “Care providers need education regarding the long-term risks associated with a history of preterm delivery in order to better educate their patients regarding both prevention of recurrent preterm birth and the development of hypertension and CVD.” However, socioeconomic status, education level, and the inability to obtain further health care remain common barriers to intervention for many women.

“Additional research is needed to identify the causes of inflammatory processes leading to preterm delivery and risks for hypertension and CVD,” said Dr. Crane. “Only after the causes are identified can treatments be sought to successfully treat these conditions.”

The study was supported by the National Heart, Lung, and Blood Institute at the National Institutes of Health; the Swedish Research Council; the Swedish Heart-Lung Foundation; and an Avtal om Läkarutbildning och Forskning (Agreement on Medical Training and Research) (ALF) project grant from Region Skåne/Lund University. Neither the researchers nor Dr. Crane had any financial conflicts to disclose.

An investigational oral form of parathyroid hormone (PTH 1-34), EB 613 (Entera Bio) met its primary efficacy outcome in a phase 2 dosing study involving postmenopausal women with low bone mineral density (BMD).

The adverse effect profile of the drug was similar to that of the injectable PTH 1-34 teriparatide (Forteo), which is approved for osteoporosis.

Arthur C. Santora, MD, chief medical officer, Entera Bio, presented 6-month findings from the study during an oral session at the annual meeting of the American Society of Bone and Mineral Research. The 3-month findings from the study were reported as a poster.

If the drug demonstrates efficacy and safety in larger phase 3 trials, it could be the first oral bone-building (anabolic) therapy for osteoporosis.

Clifford J. Rosen, MD, PhD, who was not involved with the research, told this news organization: “I think this is an intriguing study.” The most likely patients for oral PTH, he added, “are those that have osteoporosis, previous fracture, or very low BMD, particularly those unlikely or unwilling to take bisphosphonates.”

However, “this is very early in the process before this drug could come to market,” cautioned Dr. Rosen, who is director of the Center for Clinical and Translational Research, Maine Medical Research Institute, Scarborough.

“Much more data on efficacy are required at 12 and 24 months for phase 2, and then a full phase 3 [clinical trial] with high-risk fracture patients,” he said.

The company is seeking input from the Food and Drug Administration to develop the protocol for a phase 3 trial. They expect to start this trial in 2022 at sites in the United States, Europe, and Israel, Dr. Santora said.
 

Primary outcome met

The study randomly assigned 161 postmenopausal women with osteoporosis or low BMD to receive placebo or the investigational oral PTH for 6 months.

Compared with women who received placebo, those who received the study drug experienced a significantly greater increase in the bone formation marker procollagen type I N-terminal propeptide (P1NP) from baseline to 3 months, thereby meeting the study’s primary outcome.

In secondary outcomes, women who received the 2.5-mg/d dose experienced a similar 6-month increase in BMD at the spine and greater increases in BMD at the total hip and femoral neck than those who received injectable teriparatide, Dr. Santora reported.

“The study’s key takeaway is that a once-daily oral PTH [tablet] has the potential to produce the same BMD effects as subcutaneous injections of PTH,” he said in an interview.

Additionally, “the drug was well tolerated when the dose was titrated by adding additional tablets, which suggests that the dose can be tailored to each patient,” he said.
 

Other study findings

Injectable teriparatide reduces the risk for vertebral fractures by up to 80%, Dr. Santora noted, but the fact that the drug must be administered by injection may deter some older patients from using it.

The company developed an oral form of biosynthetic human PTH with a proprietary drug delivery.

The researchers conducted the phase 2 study at four sites in Israel between June 2019 and May 2021. They enrolled women aged 50 years and older who had entered menopause at least 3 years earlier and who had osteoporosis or low BMD.

Forty-three women received placebo, and the others received oral PTH at doses of 0.5 mg/d (n = 25), 1.0 mg/d (n = 29), 1.5 mg/d (n = 28), 2.5 mg/d (n = 19), or at a dose that was titrated up to 2.5 mg/d starting at 1.5 mg/d for month 1, then 2 mg/d for month 2, and then 2.5 mg/d for months 3 to 6 (n = 17).

The mean age of the patients was 61 years, the mean body mass index was 25-27 kg/m², and the mean T score at the spine of –2.2 to –2.45.

Among the women who received 2.5 mg/d of oral PTH for the full 6 months, serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) decreased 21% from baseline to 6 months, and serum levels of P1NP increased at month 1 and then decreased to baseline by month 6.

The women who received 2.5 mg/d of oral PTH for the full 6 months also demonstrated significantly greater increases in BMD at the lumbar spine (3.8%), total hip (1.4%), and femoral neck (2.4%), compared with women who received placebo.

The safety profile of oral PTH was consistent with that of subcutaneous PTH. Patients experienced headache, nausea, presyncope, and dizziness; there were no treatment-emergent hypercalcemia adverse events.
 

A few ‘unexpected findings’

Suzanne M. Jan De Beur, MD, outgoing ASBMR president, said, “Oral PTH appeared to increase BMD by [dual-energy x-ray absorptiometry] at the lumbar spine effectively and to a similar degree as teriparatide in previous studies.”

She identified two unexpected findings.

“There were increases in BMD by DXA at the femoral neck and total hip at 6 months that were [greater than those] seen in previous trials of teriparatide. Second, markers of bone resorption (CTX) decreased at 6 months, and this is in stark contrast to the increases observed with teriparatide treatment,” she noted in an interview.

Dr. Rosen also noted that “the decrease in CTX is very unusual for PTH and difficult to explain.” He added: “P1NP, a marker of bone formation, was not increased.”

Dr. Jan de Beur continued: “Teriparatide (PTH1-34) and abaloparatide are effective anabolic agents that we use to treat patients with high risk of osteoporotic fracture. Although effective, the burden of daily subcutaneous injection can be a barrier for older individuals, those with poor dexterity, and those that are averse to self-injection.

“Taken together, these results appear promising, that oral PTH may prove to be an effective anabolic agent for osteoporosis treatment,” she summarized.

She stressed that a larger phase 3 study is needed to demonstrate safety and efficacy.

The study was funded by Entera Bio. Dr. Santora is chief medical officer of Entera Bio.

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

An investigational oral form of parathyroid hormone (PTH 1-34), EB 613 (Entera Bio) met its primary efficacy outcome in a phase 2 dosing study involving postmenopausal women with low bone mineral density (BMD).

The adverse effect profile of the drug was similar to that of the injectable PTH 1-34 teriparatide (Forteo), which is approved for osteoporosis.

Arthur C. Santora, MD, chief medical officer, Entera Bio, presented 6-month findings from the study during an oral session at the annual meeting of the American Society of Bone and Mineral Research. The 3-month findings from the study were reported as a poster.

If the drug demonstrates efficacy and safety in larger phase 3 trials, it could be the first oral bone-building (anabolic) therapy for osteoporosis.

Clifford J. Rosen, MD, PhD, who was not involved with the research, told this news organization: “I think this is an intriguing study.” The most likely patients for oral PTH, he added, “are those that have osteoporosis, previous fracture, or very low BMD, particularly those unlikely or unwilling to take bisphosphonates.”

However, “this is very early in the process before this drug could come to market,” cautioned Dr. Rosen, who is director of the Center for Clinical and Translational Research, Maine Medical Research Institute, Scarborough.

“Much more data on efficacy are required at 12 and 24 months for phase 2, and then a full phase 3 [clinical trial] with high-risk fracture patients,” he said.

The company is seeking input from the Food and Drug Administration to develop the protocol for a phase 3 trial. They expect to start this trial in 2022 at sites in the United States, Europe, and Israel, Dr. Santora said.
 

Primary outcome met

The study randomly assigned 161 postmenopausal women with osteoporosis or low BMD to receive placebo or the investigational oral PTH for 6 months.

Compared with women who received placebo, those who received the study drug experienced a significantly greater increase in the bone formation marker procollagen type I N-terminal propeptide (P1NP) from baseline to 3 months, thereby meeting the study’s primary outcome.

In secondary outcomes, women who received the 2.5-mg/d dose experienced a similar 6-month increase in BMD at the spine and greater increases in BMD at the total hip and femoral neck than those who received injectable teriparatide, Dr. Santora reported.

“The study’s key takeaway is that a once-daily oral PTH [tablet] has the potential to produce the same BMD effects as subcutaneous injections of PTH,” he said in an interview.

Additionally, “the drug was well tolerated when the dose was titrated by adding additional tablets, which suggests that the dose can be tailored to each patient,” he said.
 

Other study findings

Injectable teriparatide reduces the risk for vertebral fractures by up to 80%, Dr. Santora noted, but the fact that the drug must be administered by injection may deter some older patients from using it.

The company developed an oral form of biosynthetic human PTH with a proprietary drug delivery.

The researchers conducted the phase 2 study at four sites in Israel between June 2019 and May 2021. They enrolled women aged 50 years and older who had entered menopause at least 3 years earlier and who had osteoporosis or low BMD.

Forty-three women received placebo, and the others received oral PTH at doses of 0.5 mg/d (n = 25), 1.0 mg/d (n = 29), 1.5 mg/d (n = 28), 2.5 mg/d (n = 19), or at a dose that was titrated up to 2.5 mg/d starting at 1.5 mg/d for month 1, then 2 mg/d for month 2, and then 2.5 mg/d for months 3 to 6 (n = 17).

The mean age of the patients was 61 years, the mean body mass index was 25-27 kg/m², and the mean T score at the spine of –2.2 to –2.45.

Among the women who received 2.5 mg/d of oral PTH for the full 6 months, serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) decreased 21% from baseline to 6 months, and serum levels of P1NP increased at month 1 and then decreased to baseline by month 6.

The women who received 2.5 mg/d of oral PTH for the full 6 months also demonstrated significantly greater increases in BMD at the lumbar spine (3.8%), total hip (1.4%), and femoral neck (2.4%), compared with women who received placebo.

The safety profile of oral PTH was consistent with that of subcutaneous PTH. Patients experienced headache, nausea, presyncope, and dizziness; there were no treatment-emergent hypercalcemia adverse events.
 

A few ‘unexpected findings’

Suzanne M. Jan De Beur, MD, outgoing ASBMR president, said, “Oral PTH appeared to increase BMD by [dual-energy x-ray absorptiometry] at the lumbar spine effectively and to a similar degree as teriparatide in previous studies.”

She identified two unexpected findings.

“There were increases in BMD by DXA at the femoral neck and total hip at 6 months that were [greater than those] seen in previous trials of teriparatide. Second, markers of bone resorption (CTX) decreased at 6 months, and this is in stark contrast to the increases observed with teriparatide treatment,” she noted in an interview.

Dr. Rosen also noted that “the decrease in CTX is very unusual for PTH and difficult to explain.” He added: “P1NP, a marker of bone formation, was not increased.”

Dr. Jan de Beur continued: “Teriparatide (PTH1-34) and abaloparatide are effective anabolic agents that we use to treat patients with high risk of osteoporotic fracture. Although effective, the burden of daily subcutaneous injection can be a barrier for older individuals, those with poor dexterity, and those that are averse to self-injection.

“Taken together, these results appear promising, that oral PTH may prove to be an effective anabolic agent for osteoporosis treatment,” she summarized.

She stressed that a larger phase 3 study is needed to demonstrate safety and efficacy.

The study was funded by Entera Bio. Dr. Santora is chief medical officer of Entera Bio.

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

An investigational oral form of parathyroid hormone (PTH 1-34), EB 613 (Entera Bio) met its primary efficacy outcome in a phase 2 dosing study involving postmenopausal women with low bone mineral density (BMD).

The adverse effect profile of the drug was similar to that of the injectable PTH 1-34 teriparatide (Forteo), which is approved for osteoporosis.

Arthur C. Santora, MD, chief medical officer, Entera Bio, presented 6-month findings from the study during an oral session at the annual meeting of the American Society of Bone and Mineral Research. The 3-month findings from the study were reported as a poster.

If the drug demonstrates efficacy and safety in larger phase 3 trials, it could be the first oral bone-building (anabolic) therapy for osteoporosis.

Clifford J. Rosen, MD, PhD, who was not involved with the research, told this news organization: “I think this is an intriguing study.” The most likely patients for oral PTH, he added, “are those that have osteoporosis, previous fracture, or very low BMD, particularly those unlikely or unwilling to take bisphosphonates.”

However, “this is very early in the process before this drug could come to market,” cautioned Dr. Rosen, who is director of the Center for Clinical and Translational Research, Maine Medical Research Institute, Scarborough.

“Much more data on efficacy are required at 12 and 24 months for phase 2, and then a full phase 3 [clinical trial] with high-risk fracture patients,” he said.

The company is seeking input from the Food and Drug Administration to develop the protocol for a phase 3 trial. They expect to start this trial in 2022 at sites in the United States, Europe, and Israel, Dr. Santora said.
 

Primary outcome met

The study randomly assigned 161 postmenopausal women with osteoporosis or low BMD to receive placebo or the investigational oral PTH for 6 months.

Compared with women who received placebo, those who received the study drug experienced a significantly greater increase in the bone formation marker procollagen type I N-terminal propeptide (P1NP) from baseline to 3 months, thereby meeting the study’s primary outcome.

In secondary outcomes, women who received the 2.5-mg/d dose experienced a similar 6-month increase in BMD at the spine and greater increases in BMD at the total hip and femoral neck than those who received injectable teriparatide, Dr. Santora reported.

“The study’s key takeaway is that a once-daily oral PTH [tablet] has the potential to produce the same BMD effects as subcutaneous injections of PTH,” he said in an interview.

Additionally, “the drug was well tolerated when the dose was titrated by adding additional tablets, which suggests that the dose can be tailored to each patient,” he said.
 

Other study findings

Injectable teriparatide reduces the risk for vertebral fractures by up to 80%, Dr. Santora noted, but the fact that the drug must be administered by injection may deter some older patients from using it.

The company developed an oral form of biosynthetic human PTH with a proprietary drug delivery.

The researchers conducted the phase 2 study at four sites in Israel between June 2019 and May 2021. They enrolled women aged 50 years and older who had entered menopause at least 3 years earlier and who had osteoporosis or low BMD.

Forty-three women received placebo, and the others received oral PTH at doses of 0.5 mg/d (n = 25), 1.0 mg/d (n = 29), 1.5 mg/d (n = 28), 2.5 mg/d (n = 19), or at a dose that was titrated up to 2.5 mg/d starting at 1.5 mg/d for month 1, then 2 mg/d for month 2, and then 2.5 mg/d for months 3 to 6 (n = 17).

The mean age of the patients was 61 years, the mean body mass index was 25-27 kg/m², and the mean T score at the spine of –2.2 to –2.45.

Among the women who received 2.5 mg/d of oral PTH for the full 6 months, serum levels of the bone resorption marker C-terminal telopeptide of type I collagen (CTX) decreased 21% from baseline to 6 months, and serum levels of P1NP increased at month 1 and then decreased to baseline by month 6.

The women who received 2.5 mg/d of oral PTH for the full 6 months also demonstrated significantly greater increases in BMD at the lumbar spine (3.8%), total hip (1.4%), and femoral neck (2.4%), compared with women who received placebo.

The safety profile of oral PTH was consistent with that of subcutaneous PTH. Patients experienced headache, nausea, presyncope, and dizziness; there were no treatment-emergent hypercalcemia adverse events.
 

A few ‘unexpected findings’

Suzanne M. Jan De Beur, MD, outgoing ASBMR president, said, “Oral PTH appeared to increase BMD by [dual-energy x-ray absorptiometry] at the lumbar spine effectively and to a similar degree as teriparatide in previous studies.”

She identified two unexpected findings.

“There were increases in BMD by DXA at the femoral neck and total hip at 6 months that were [greater than those] seen in previous trials of teriparatide. Second, markers of bone resorption (CTX) decreased at 6 months, and this is in stark contrast to the increases observed with teriparatide treatment,” she noted in an interview.

Dr. Rosen also noted that “the decrease in CTX is very unusual for PTH and difficult to explain.” He added: “P1NP, a marker of bone formation, was not increased.”

Dr. Jan de Beur continued: “Teriparatide (PTH1-34) and abaloparatide are effective anabolic agents that we use to treat patients with high risk of osteoporotic fracture. Although effective, the burden of daily subcutaneous injection can be a barrier for older individuals, those with poor dexterity, and those that are averse to self-injection.

“Taken together, these results appear promising, that oral PTH may prove to be an effective anabolic agent for osteoporosis treatment,” she summarized.

She stressed that a larger phase 3 study is needed to demonstrate safety and efficacy.

The study was funded by Entera Bio. Dr. Santora is chief medical officer of Entera Bio.

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