Osteoporosis

The vitamin D story exudes teaching points: It offers a master class in critical appraisal, connecting the concepts of biologic plausibility, flawed surrogate markers, confounded observational studies, and slews of randomized controlled trials (RCTs) showing no benefits on health outcomes.

Yet despite the utter lack of benefit seen in trials, the hype continues. And the pandemic has only enhanced this hype as an onslaught of papers have reported the association of low vitamin D levels and COVID-19 disease.

My questions are simple: Why doesn’t the evidence persuade people? How many nonsignificant trials do we need before researchers stop studying vitamin D, doctors stop (routinely) measuring levels, and patients stop wasting money on the unhelpful supplement? What are the implications for this lack of persuasion?

Before exploring these questions, I want to set out that symptomatic vitamin deficiencies of any sort ought to be corrected. 
 

Biologic plausibility and the pull of observational studies

It has long been known that vitamin D is crucial for bone health and that it can be produced in the skin with sun exposure. In the last decade, however, experts note that nearly every tissue and cell in our body has a vitamin D receptor. It then follows that if this many cells in the body can activate vitamin D, it must be vital for cardiovascular health, immune function, cancer prevention: basically, everything health related.

Oodles of observational studies have found that low serum levels of vitamin D correlate with higher mortality from all causes, cancer, cardiovascular disease, and now even COVID-19. Yet no matter the amount of statistical adjustment in these studies, we cannot know whether these associations are due to true causality.

The major issue is confounding: That is, people with low vitamin D levels have other conditions or diseases that lead to higher rates of ill health. Consider a patient with obesity, arthritis, and cognitive decline; this person is unlikely to do much exercise in the sun and may have low vitamin D levels. The low vitamin D level is simply a marker of overall poor health.
 

The randomized controlled trials tell a clear story

There are hundreds of vitamin D RCTs. The results simplify into one sentence: Vitamin D supplements do not improve health outcomes.

Here is a short summary of some recent studies.

VITAL, a massive (N > 25,000) RCT with 5 years of follow-up, compared vitamin D supplements to placebo and found no differences in the primary endpoints of cancer or cardiac events. Rates of death from any cause were nearly identical. Crucially, in subgroup analyses, the effects did not vary according to vitamin D levels at baseline.

The D-Health investigators randomly assigned more than 21,000 adults to vitamin D or placebo and after 5.7 years of follow-up reported no differences in the primary endpoint of overall mortality. There also were no differences in cardiovascular disease mortality.

Then you have the Mendelian randomized studies, which some have called nature’s RCT. These studies take advantage of the fact that some people are born with gene variations that predispose to low vitamin D levels. More than 60 Mendelian randomization studies have evaluated the consequences of lifelong genetically lowered vitamin D levels on various outcomes; most of these have found null effects.

Then there are the meta-analyses and systematic reviews. I loved the conclusion of this review of systematic reviews from the BMJ (emphasis mine):

“Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable.”

 

The failure to persuade

My original plan was to emphasize the power of the RCT. Despite strong associations of low vitamin D levels with poor outcomes, the trials show no benefit to treatment. This strongly suggests (or nearly proves) that low vitamin D levels are akin to premature ventricular complexes after myocardial infarction: a marker for risk but not a target for therapy.

But I now see the more important issue as why scientists, funders, clinicians, and patients are not persuaded by clear evidence. Every day in clinic I see patients on vitamin D supplements; the journals keep publishing vitamin D studies. The proponents of vitamin D remain positive. And lately there is outsized attention and hope that vitamin D will mitigate SARS-CoV2 infection – based only on observational data.

You might argue against this point by saying vitamin D is natural and relatively innocuous, so who cares?

I offer three rebuttals to that point: Opportunity costs, distraction, and the insidious danger of poor critical appraisal skills. If you are burning money on vitamin D research, there is less available to study other important issues. If a patient is distracted by low vitamin D levels, she may pay less attention to her high body mass index or hypertension. And on the matter of critical appraisal, trust in medicine requires clinicians to be competent in critical appraisal. And these days, what could be more important than trust in medical professionals?

One major reason for the failure of persuasion of evidence is spin – or language that distracts from the primary endpoint. Here are two (of many) examples:

A meta-analysis of 50 vitamin D trials set out to study mortality. The authors found no significant difference in that primary endpoint. But the second sentence in their conclusion was that vitamin D supplements reduced the risk for cancer deaths by 15%. That’s a secondary endpoint in a study with nonsignificance in the primary endpoint. That is spin. This meta-analysis was completed before the Australian D-Health trial found that cancer deaths were 15% higher in the vitamin D arm, a difference that did not reach statistical significance.

The following example is worse: The authors of the VITAL trial, which found that vitamin D supplements had no effect on the primary endpoint of invasive cancer or cardiovascular disease, published a secondary analysis of the trial looking at a different endpoint: A composite incidence of metastatic and fatal invasive total cancer. They reported a 0.4% lower rate for the vitamin D group, a difference that barely made statistical significance at a P value of .04. 

But everyone knows the dangers of reanalyzing data with a new endpoint after you have seen the data. What’s more, even if this were a reasonable post hoc analysis, the results are neither clinically meaningful nor statistically robust.  Yet the fatally flawed paper has been viewed 60,000 times and picked up by 48 news outlets.

Another way to distract from nonsignificant primary outcomes is to nitpick the trials. The vitamin D dose wasn’t high enough, for instance. This might persuade me if there were one or two vitamin D trials, but there are hundreds of trials and meta-analyses, and their results are consistently null.
 

Conclusion: No, it is not hopeless

A nihilist would argue that fighting spin is futile. They would say you can’t fight incentives and business models. The incentive structure to publish is strong, and the journals and media know vitamin D studies garner attention – which is their currency.

I am not a nihilist and believe strongly that we must continue to teach critical appraisal and numerical literacy.

In fact, I would speculate that decades of poor critical appraisal by the medical profession have fostered outsized hope and created erroneous norms.

Imagine a counter-factual world in which clinicians have taught society that the human body is unlike an engine that can be repaired by fixing one part (i.e., the vitamin D level), that magic bullets (insulin) are rare, that most treatments fail, or that you can’t rely on association studies to prove efficacy.

In this world, people would be immune from spin and hype.

The norm would be that pills, supplements, and procedures are not what delivers good health. What delivers health is an amalgam of good luck, healthy habits, and lots of time spent outside playing in the sun.
 

Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky., and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. He has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

The vitamin D story exudes teaching points: It offers a master class in critical appraisal, connecting the concepts of biologic plausibility, flawed surrogate markers, confounded observational studies, and slews of randomized controlled trials (RCTs) showing no benefits on health outcomes.

Yet despite the utter lack of benefit seen in trials, the hype continues. And the pandemic has only enhanced this hype as an onslaught of papers have reported the association of low vitamin D levels and COVID-19 disease.

My questions are simple: Why doesn’t the evidence persuade people? How many nonsignificant trials do we need before researchers stop studying vitamin D, doctors stop (routinely) measuring levels, and patients stop wasting money on the unhelpful supplement? What are the implications for this lack of persuasion?

Before exploring these questions, I want to set out that symptomatic vitamin deficiencies of any sort ought to be corrected. 
 

Biologic plausibility and the pull of observational studies

It has long been known that vitamin D is crucial for bone health and that it can be produced in the skin with sun exposure. In the last decade, however, experts note that nearly every tissue and cell in our body has a vitamin D receptor. It then follows that if this many cells in the body can activate vitamin D, it must be vital for cardiovascular health, immune function, cancer prevention: basically, everything health related.

Oodles of observational studies have found that low serum levels of vitamin D correlate with higher mortality from all causes, cancer, cardiovascular disease, and now even COVID-19. Yet no matter the amount of statistical adjustment in these studies, we cannot know whether these associations are due to true causality.

The major issue is confounding: That is, people with low vitamin D levels have other conditions or diseases that lead to higher rates of ill health. Consider a patient with obesity, arthritis, and cognitive decline; this person is unlikely to do much exercise in the sun and may have low vitamin D levels. The low vitamin D level is simply a marker of overall poor health.
 

The randomized controlled trials tell a clear story

There are hundreds of vitamin D RCTs. The results simplify into one sentence: Vitamin D supplements do not improve health outcomes.

Here is a short summary of some recent studies.

VITAL, a massive (N > 25,000) RCT with 5 years of follow-up, compared vitamin D supplements to placebo and found no differences in the primary endpoints of cancer or cardiac events. Rates of death from any cause were nearly identical. Crucially, in subgroup analyses, the effects did not vary according to vitamin D levels at baseline.

The D-Health investigators randomly assigned more than 21,000 adults to vitamin D or placebo and after 5.7 years of follow-up reported no differences in the primary endpoint of overall mortality. There also were no differences in cardiovascular disease mortality.

Then you have the Mendelian randomized studies, which some have called nature’s RCT. These studies take advantage of the fact that some people are born with gene variations that predispose to low vitamin D levels. More than 60 Mendelian randomization studies have evaluated the consequences of lifelong genetically lowered vitamin D levels on various outcomes; most of these have found null effects.

Then there are the meta-analyses and systematic reviews. I loved the conclusion of this review of systematic reviews from the BMJ (emphasis mine):

“Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable.”

 

The failure to persuade

My original plan was to emphasize the power of the RCT. Despite strong associations of low vitamin D levels with poor outcomes, the trials show no benefit to treatment. This strongly suggests (or nearly proves) that low vitamin D levels are akin to premature ventricular complexes after myocardial infarction: a marker for risk but not a target for therapy.

But I now see the more important issue as why scientists, funders, clinicians, and patients are not persuaded by clear evidence. Every day in clinic I see patients on vitamin D supplements; the journals keep publishing vitamin D studies. The proponents of vitamin D remain positive. And lately there is outsized attention and hope that vitamin D will mitigate SARS-CoV2 infection – based only on observational data.

You might argue against this point by saying vitamin D is natural and relatively innocuous, so who cares?

I offer three rebuttals to that point: Opportunity costs, distraction, and the insidious danger of poor critical appraisal skills. If you are burning money on vitamin D research, there is less available to study other important issues. If a patient is distracted by low vitamin D levels, she may pay less attention to her high body mass index or hypertension. And on the matter of critical appraisal, trust in medicine requires clinicians to be competent in critical appraisal. And these days, what could be more important than trust in medical professionals?

One major reason for the failure of persuasion of evidence is spin – or language that distracts from the primary endpoint. Here are two (of many) examples:

A meta-analysis of 50 vitamin D trials set out to study mortality. The authors found no significant difference in that primary endpoint. But the second sentence in their conclusion was that vitamin D supplements reduced the risk for cancer deaths by 15%. That’s a secondary endpoint in a study with nonsignificance in the primary endpoint. That is spin. This meta-analysis was completed before the Australian D-Health trial found that cancer deaths were 15% higher in the vitamin D arm, a difference that did not reach statistical significance.

The following example is worse: The authors of the VITAL trial, which found that vitamin D supplements had no effect on the primary endpoint of invasive cancer or cardiovascular disease, published a secondary analysis of the trial looking at a different endpoint: A composite incidence of metastatic and fatal invasive total cancer. They reported a 0.4% lower rate for the vitamin D group, a difference that barely made statistical significance at a P value of .04. 

But everyone knows the dangers of reanalyzing data with a new endpoint after you have seen the data. What’s more, even if this were a reasonable post hoc analysis, the results are neither clinically meaningful nor statistically robust.  Yet the fatally flawed paper has been viewed 60,000 times and picked up by 48 news outlets.

Another way to distract from nonsignificant primary outcomes is to nitpick the trials. The vitamin D dose wasn’t high enough, for instance. This might persuade me if there were one or two vitamin D trials, but there are hundreds of trials and meta-analyses, and their results are consistently null.
 

Conclusion: No, it is not hopeless

A nihilist would argue that fighting spin is futile. They would say you can’t fight incentives and business models. The incentive structure to publish is strong, and the journals and media know vitamin D studies garner attention – which is their currency.

I am not a nihilist and believe strongly that we must continue to teach critical appraisal and numerical literacy.

In fact, I would speculate that decades of poor critical appraisal by the medical profession have fostered outsized hope and created erroneous norms.

Imagine a counter-factual world in which clinicians have taught society that the human body is unlike an engine that can be repaired by fixing one part (i.e., the vitamin D level), that magic bullets (insulin) are rare, that most treatments fail, or that you can’t rely on association studies to prove efficacy.

In this world, people would be immune from spin and hype.

The norm would be that pills, supplements, and procedures are not what delivers good health. What delivers health is an amalgam of good luck, healthy habits, and lots of time spent outside playing in the sun.
 

Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky., and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. He has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

The vitamin D story exudes teaching points: It offers a master class in critical appraisal, connecting the concepts of biologic plausibility, flawed surrogate markers, confounded observational studies, and slews of randomized controlled trials (RCTs) showing no benefits on health outcomes.

Yet despite the utter lack of benefit seen in trials, the hype continues. And the pandemic has only enhanced this hype as an onslaught of papers have reported the association of low vitamin D levels and COVID-19 disease.

My questions are simple: Why doesn’t the evidence persuade people? How many nonsignificant trials do we need before researchers stop studying vitamin D, doctors stop (routinely) measuring levels, and patients stop wasting money on the unhelpful supplement? What are the implications for this lack of persuasion?

Before exploring these questions, I want to set out that symptomatic vitamin deficiencies of any sort ought to be corrected. 
 

Biologic plausibility and the pull of observational studies

It has long been known that vitamin D is crucial for bone health and that it can be produced in the skin with sun exposure. In the last decade, however, experts note that nearly every tissue and cell in our body has a vitamin D receptor. It then follows that if this many cells in the body can activate vitamin D, it must be vital for cardiovascular health, immune function, cancer prevention: basically, everything health related.

Oodles of observational studies have found that low serum levels of vitamin D correlate with higher mortality from all causes, cancer, cardiovascular disease, and now even COVID-19. Yet no matter the amount of statistical adjustment in these studies, we cannot know whether these associations are due to true causality.

The major issue is confounding: That is, people with low vitamin D levels have other conditions or diseases that lead to higher rates of ill health. Consider a patient with obesity, arthritis, and cognitive decline; this person is unlikely to do much exercise in the sun and may have low vitamin D levels. The low vitamin D level is simply a marker of overall poor health.
 

The randomized controlled trials tell a clear story

There are hundreds of vitamin D RCTs. The results simplify into one sentence: Vitamin D supplements do not improve health outcomes.

Here is a short summary of some recent studies.

VITAL, a massive (N > 25,000) RCT with 5 years of follow-up, compared vitamin D supplements to placebo and found no differences in the primary endpoints of cancer or cardiac events. Rates of death from any cause were nearly identical. Crucially, in subgroup analyses, the effects did not vary according to vitamin D levels at baseline.

The D-Health investigators randomly assigned more than 21,000 adults to vitamin D or placebo and after 5.7 years of follow-up reported no differences in the primary endpoint of overall mortality. There also were no differences in cardiovascular disease mortality.

Then you have the Mendelian randomized studies, which some have called nature’s RCT. These studies take advantage of the fact that some people are born with gene variations that predispose to low vitamin D levels. More than 60 Mendelian randomization studies have evaluated the consequences of lifelong genetically lowered vitamin D levels on various outcomes; most of these have found null effects.

Then there are the meta-analyses and systematic reviews. I loved the conclusion of this review of systematic reviews from the BMJ (emphasis mine):

“Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable.”

 

The failure to persuade

My original plan was to emphasize the power of the RCT. Despite strong associations of low vitamin D levels with poor outcomes, the trials show no benefit to treatment. This strongly suggests (or nearly proves) that low vitamin D levels are akin to premature ventricular complexes after myocardial infarction: a marker for risk but not a target for therapy.

But I now see the more important issue as why scientists, funders, clinicians, and patients are not persuaded by clear evidence. Every day in clinic I see patients on vitamin D supplements; the journals keep publishing vitamin D studies. The proponents of vitamin D remain positive. And lately there is outsized attention and hope that vitamin D will mitigate SARS-CoV2 infection – based only on observational data.

You might argue against this point by saying vitamin D is natural and relatively innocuous, so who cares?

I offer three rebuttals to that point: Opportunity costs, distraction, and the insidious danger of poor critical appraisal skills. If you are burning money on vitamin D research, there is less available to study other important issues. If a patient is distracted by low vitamin D levels, she may pay less attention to her high body mass index or hypertension. And on the matter of critical appraisal, trust in medicine requires clinicians to be competent in critical appraisal. And these days, what could be more important than trust in medical professionals?

One major reason for the failure of persuasion of evidence is spin – or language that distracts from the primary endpoint. Here are two (of many) examples:

A meta-analysis of 50 vitamin D trials set out to study mortality. The authors found no significant difference in that primary endpoint. But the second sentence in their conclusion was that vitamin D supplements reduced the risk for cancer deaths by 15%. That’s a secondary endpoint in a study with nonsignificance in the primary endpoint. That is spin. This meta-analysis was completed before the Australian D-Health trial found that cancer deaths were 15% higher in the vitamin D arm, a difference that did not reach statistical significance.

The following example is worse: The authors of the VITAL trial, which found that vitamin D supplements had no effect on the primary endpoint of invasive cancer or cardiovascular disease, published a secondary analysis of the trial looking at a different endpoint: A composite incidence of metastatic and fatal invasive total cancer. They reported a 0.4% lower rate for the vitamin D group, a difference that barely made statistical significance at a P value of .04. 

But everyone knows the dangers of reanalyzing data with a new endpoint after you have seen the data. What’s more, even if this were a reasonable post hoc analysis, the results are neither clinically meaningful nor statistically robust.  Yet the fatally flawed paper has been viewed 60,000 times and picked up by 48 news outlets.

Another way to distract from nonsignificant primary outcomes is to nitpick the trials. The vitamin D dose wasn’t high enough, for instance. This might persuade me if there were one or two vitamin D trials, but there are hundreds of trials and meta-analyses, and their results are consistently null.
 

Conclusion: No, it is not hopeless

A nihilist would argue that fighting spin is futile. They would say you can’t fight incentives and business models. The incentive structure to publish is strong, and the journals and media know vitamin D studies garner attention – which is their currency.

I am not a nihilist and believe strongly that we must continue to teach critical appraisal and numerical literacy.

In fact, I would speculate that decades of poor critical appraisal by the medical profession have fostered outsized hope and created erroneous norms.

Imagine a counter-factual world in which clinicians have taught society that the human body is unlike an engine that can be repaired by fixing one part (i.e., the vitamin D level), that magic bullets (insulin) are rare, that most treatments fail, or that you can’t rely on association studies to prove efficacy.

In this world, people would be immune from spin and hype.

The norm would be that pills, supplements, and procedures are not what delivers good health. What delivers health is an amalgam of good luck, healthy habits, and lots of time spent outside playing in the sun.
 

Dr. Mandrola practices cardiac electrophysiology in Louisville, Ky., and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. He has disclosed no relevant financial relationships. A version of this article first appeared on Medscape.com.

Contrary to conventional clinical wisdom, greater body fat is associated with lower bone mineral density (BMD), particularly in men, an analysis of data from a large, nationally representative sample has found.  

Much previous research has suggested that obesity protects against fractures and loss of BMD for a variety of reasons, including the beneficial effects of weight-bearing on the skeleton and hormonal factors linked to body fat. But the new findings should prompt a reconsideration of the relationship between obesity and fracture risk, according to the investigators, whose study appears in the Journal of Clinical Endocrinology & Metabolism.

“While higher BMI [body mass index] is generally associated with higher bone density, our study demonstrates that lean and fat mass affect bone density differently and that obesity is not a guarantee against osteoporosis,” Rajesh K. Jain, MD, of the University of Chicago said in an interview.

Dr. Jain and a colleague, Tamara Vokes, MD, used multivariant modeling to examine the relationship between BMD and body composition of 10,814 men and women aged 20-59 years from the National Health and Nutrition Examination Survey (NHANES) 2011-2018. All underwent total body dual-energy x-ray absorptiometry scans.

Participants were stratified into sex-specific quartiles based on lean mass index (LMI; lean mass divided by height squared) and fat mass index (FMI; fat mass divided by height squared). Lean mass had a strong positive association with bone density, whereas fat mass had a moderate negative effect, the researchers found.

An additional kg/m² of FMI was associated with a 0.10 lower T score, the number of standard deviations from the expected bone density of a young adult (P < .001). The negative effect was greater in men, who had a 0.13 lower T score per additional 1 kg/m² of FMI, compared with 0.08 lower in women (P < .001). The effect was most pronounced in people in the highest FMI quartile.

Body composition is not a routine clinical measurement, Dr. Jain and Dr. Vokes noted. Prior studies of the effect of body composition on bone density have been limited by small patient numbers, referral bias, lack of racial or ethnic diversity, and the use of estimates rather than true measures of fat and lean tissue. NHANES is designed to mirror the U.S. population.

The researchers say when it comes to patients with obesity, the findings “should not dissuade clinicians from assessing bone density, particularly if other risk factors are present.”
 

Useful clinical proxies for body composition

Clinicians have no routine way to measure body composition in an office setting. As a result, Dr. Jain advised clinicians to look at factors that correlate with high body fat, such as the presence of diabetes, or with low lean mass, such as poor performance on physical activity measures like grip strength, when deciding whether to consider osteoporosis screening. Patients with obesity should undergo recommended bone density screening, especially if they have other risk factors such as older age, previous fracture, steroid use, or a family history of fracture.

Although some extra weight may have a beneficial loading effect, too much extra weight can lead to metabolic problems and restrict movement, according to Rodrigo J. Valderrábano, MD, medical director of clinical research for the Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital in Boston. “There’s a general sense that the extra weight is only good for your bones if you can carry it around,” said Dr. Valderrábano, who was not involved in the study.

More research is needed to understand why fat affects men and women differently, Dr. Jain noted. The researchers found that testosterone and estradiol values did not fully explain the variation.

Adipokines released by fat cells may be important in driving bone loss but were not measured in the study, Peter R. Ebeling, MD, president of the American Society of Bone and Mineral Research, said in an interview. Distribution of fractures in obesity suggests that a high FMI may preferentially affect cortical bone instead of trabecular bone, but further studies using high-resolution peripheral quantitative CT are required to confirm the difference.

Dr. Ebeling, who was not involved in the new study, agreed that the positive relationship between BMI and BMD has led to false reassurance that people with obesity may be protected from fragility fractures. “The take-home message for clinicians is that we should not neglect bone health in our patients with obesity, both male and female.”

Dr. Jain has reported receiving grant support from the Amgen Foundation and being a consultant for Radius Health. Dr. Vokes has reported being an investigator, consultant, and speaker for Radius Health, investigator and consultant for Takeda Pharmaceutical, and investigator for Ascendis Pharma. Dr. Valderrábano and Dr. Ebeling reported no relevant financial relationships.

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

Contrary to conventional clinical wisdom, greater body fat is associated with lower bone mineral density (BMD), particularly in men, an analysis of data from a large, nationally representative sample has found.  

Much previous research has suggested that obesity protects against fractures and loss of BMD for a variety of reasons, including the beneficial effects of weight-bearing on the skeleton and hormonal factors linked to body fat. But the new findings should prompt a reconsideration of the relationship between obesity and fracture risk, according to the investigators, whose study appears in the Journal of Clinical Endocrinology & Metabolism.

“While higher BMI [body mass index] is generally associated with higher bone density, our study demonstrates that lean and fat mass affect bone density differently and that obesity is not a guarantee against osteoporosis,” Rajesh K. Jain, MD, of the University of Chicago said in an interview.

Dr. Jain and a colleague, Tamara Vokes, MD, used multivariant modeling to examine the relationship between BMD and body composition of 10,814 men and women aged 20-59 years from the National Health and Nutrition Examination Survey (NHANES) 2011-2018. All underwent total body dual-energy x-ray absorptiometry scans.

Participants were stratified into sex-specific quartiles based on lean mass index (LMI; lean mass divided by height squared) and fat mass index (FMI; fat mass divided by height squared). Lean mass had a strong positive association with bone density, whereas fat mass had a moderate negative effect, the researchers found.

An additional kg/m² of FMI was associated with a 0.10 lower T score, the number of standard deviations from the expected bone density of a young adult (P < .001). The negative effect was greater in men, who had a 0.13 lower T score per additional 1 kg/m² of FMI, compared with 0.08 lower in women (P < .001). The effect was most pronounced in people in the highest FMI quartile.

Body composition is not a routine clinical measurement, Dr. Jain and Dr. Vokes noted. Prior studies of the effect of body composition on bone density have been limited by small patient numbers, referral bias, lack of racial or ethnic diversity, and the use of estimates rather than true measures of fat and lean tissue. NHANES is designed to mirror the U.S. population.

The researchers say when it comes to patients with obesity, the findings “should not dissuade clinicians from assessing bone density, particularly if other risk factors are present.”
 

Useful clinical proxies for body composition

Clinicians have no routine way to measure body composition in an office setting. As a result, Dr. Jain advised clinicians to look at factors that correlate with high body fat, such as the presence of diabetes, or with low lean mass, such as poor performance on physical activity measures like grip strength, when deciding whether to consider osteoporosis screening. Patients with obesity should undergo recommended bone density screening, especially if they have other risk factors such as older age, previous fracture, steroid use, or a family history of fracture.

Although some extra weight may have a beneficial loading effect, too much extra weight can lead to metabolic problems and restrict movement, according to Rodrigo J. Valderrábano, MD, medical director of clinical research for the Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital in Boston. “There’s a general sense that the extra weight is only good for your bones if you can carry it around,” said Dr. Valderrábano, who was not involved in the study.

More research is needed to understand why fat affects men and women differently, Dr. Jain noted. The researchers found that testosterone and estradiol values did not fully explain the variation.

Adipokines released by fat cells may be important in driving bone loss but were not measured in the study, Peter R. Ebeling, MD, president of the American Society of Bone and Mineral Research, said in an interview. Distribution of fractures in obesity suggests that a high FMI may preferentially affect cortical bone instead of trabecular bone, but further studies using high-resolution peripheral quantitative CT are required to confirm the difference.

Dr. Ebeling, who was not involved in the new study, agreed that the positive relationship between BMI and BMD has led to false reassurance that people with obesity may be protected from fragility fractures. “The take-home message for clinicians is that we should not neglect bone health in our patients with obesity, both male and female.”

Dr. Jain has reported receiving grant support from the Amgen Foundation and being a consultant for Radius Health. Dr. Vokes has reported being an investigator, consultant, and speaker for Radius Health, investigator and consultant for Takeda Pharmaceutical, and investigator for Ascendis Pharma. Dr. Valderrábano and Dr. Ebeling reported no relevant financial relationships.

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

Contrary to conventional clinical wisdom, greater body fat is associated with lower bone mineral density (BMD), particularly in men, an analysis of data from a large, nationally representative sample has found.  

Much previous research has suggested that obesity protects against fractures and loss of BMD for a variety of reasons, including the beneficial effects of weight-bearing on the skeleton and hormonal factors linked to body fat. But the new findings should prompt a reconsideration of the relationship between obesity and fracture risk, according to the investigators, whose study appears in the Journal of Clinical Endocrinology & Metabolism.

“While higher BMI [body mass index] is generally associated with higher bone density, our study demonstrates that lean and fat mass affect bone density differently and that obesity is not a guarantee against osteoporosis,” Rajesh K. Jain, MD, of the University of Chicago said in an interview.

Dr. Jain and a colleague, Tamara Vokes, MD, used multivariant modeling to examine the relationship between BMD and body composition of 10,814 men and women aged 20-59 years from the National Health and Nutrition Examination Survey (NHANES) 2011-2018. All underwent total body dual-energy x-ray absorptiometry scans.

Participants were stratified into sex-specific quartiles based on lean mass index (LMI; lean mass divided by height squared) and fat mass index (FMI; fat mass divided by height squared). Lean mass had a strong positive association with bone density, whereas fat mass had a moderate negative effect, the researchers found.

An additional kg/m² of FMI was associated with a 0.10 lower T score, the number of standard deviations from the expected bone density of a young adult (P < .001). The negative effect was greater in men, who had a 0.13 lower T score per additional 1 kg/m² of FMI, compared with 0.08 lower in women (P < .001). The effect was most pronounced in people in the highest FMI quartile.

Body composition is not a routine clinical measurement, Dr. Jain and Dr. Vokes noted. Prior studies of the effect of body composition on bone density have been limited by small patient numbers, referral bias, lack of racial or ethnic diversity, and the use of estimates rather than true measures of fat and lean tissue. NHANES is designed to mirror the U.S. population.

The researchers say when it comes to patients with obesity, the findings “should not dissuade clinicians from assessing bone density, particularly if other risk factors are present.”
 

Useful clinical proxies for body composition

Clinicians have no routine way to measure body composition in an office setting. As a result, Dr. Jain advised clinicians to look at factors that correlate with high body fat, such as the presence of diabetes, or with low lean mass, such as poor performance on physical activity measures like grip strength, when deciding whether to consider osteoporosis screening. Patients with obesity should undergo recommended bone density screening, especially if they have other risk factors such as older age, previous fracture, steroid use, or a family history of fracture.

Although some extra weight may have a beneficial loading effect, too much extra weight can lead to metabolic problems and restrict movement, according to Rodrigo J. Valderrábano, MD, medical director of clinical research for the Research Program in Men’s Health: Aging and Metabolism, Brigham and Women’s Hospital in Boston. “There’s a general sense that the extra weight is only good for your bones if you can carry it around,” said Dr. Valderrábano, who was not involved in the study.

More research is needed to understand why fat affects men and women differently, Dr. Jain noted. The researchers found that testosterone and estradiol values did not fully explain the variation.

Adipokines released by fat cells may be important in driving bone loss but were not measured in the study, Peter R. Ebeling, MD, president of the American Society of Bone and Mineral Research, said in an interview. Distribution of fractures in obesity suggests that a high FMI may preferentially affect cortical bone instead of trabecular bone, but further studies using high-resolution peripheral quantitative CT are required to confirm the difference.

Dr. Ebeling, who was not involved in the new study, agreed that the positive relationship between BMI and BMD has led to false reassurance that people with obesity may be protected from fragility fractures. “The take-home message for clinicians is that we should not neglect bone health in our patients with obesity, both male and female.”

Dr. Jain has reported receiving grant support from the Amgen Foundation and being a consultant for Radius Health. Dr. Vokes has reported being an investigator, consultant, and speaker for Radius Health, investigator and consultant for Takeda Pharmaceutical, and investigator for Ascendis Pharma. Dr. Valderrábano and Dr. Ebeling 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.

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.

Low vitamin D is common in patients with first-episode psychosis (FEP), but supplementation does not appear to improve mental or physical symptoms, new data show.

“Previous work, our own and others, has shown that people with psychosis, even soon after their first diagnosis, have low vitamin D levels, but it was not known whether supplementing with vitamin D in people with early psychosis would improve health outcomes,” study investigator Fiona Gaughran, MD, with the Institute of Psychiatry, Psychology & Neuroscience, King’s College London, told this news organization.

“While we did not demonstrate a benefit of supplementation over 6 months, these very high rates of vitamin deficiency and insufficiency may have longer-term negative health impacts which we have not measured, so raising awareness of the need to optimize vitamin D in people with psychosis is important,” said Dr. Gaughran.

The results of the randomized clinical trial were published online Dec. 28 in JAMA Network Open.

Thoughtful approach, negative result

Participants included 149 adults within 3 years of a first presentation with a functional psychotic disorder. The cohort’s mean age was 28 years, 60% were men, 44% were Black or of other racial and ethnic minority groups, and 56% were White.

Seventy-five participants were randomly assigned to receive 120,000 IU of cholecalciferol or matching placebo administered by the researchers in monthly doses with an oral syringe.

“We chose a dose of 120,000 IU monthly (equivalent to 4,000 IU daily) which was expected to safely increase vitamin D levels. The regimen was discussed with experts with lived experience, and took into account that a daily preparation would add to the significant medication load that people with psychosis already carry,” said Dr. Gaughran.

Vitamin D supplementation as administered in this study was safe and led to a significant increase in 25-hydroxyvitamin D concentrations.

However, there was no significant difference between vitamin D and placebo in the primary outcome of total Positive and Negative Syndrome Scale (PANSS) score at 6 months (mean difference, 3.57; 95% confidence interval, –1.11 to 8.25; P = .13).

There was also no apparent benefit of vitamin D supplementation on any secondary outcome, including the PANSS subscores of global function and depression or cardiometabolic risk factors.

“With respect to clinical practice, we cannot now recommend monthly treatments with 120,000 IU of cholecalciferol in FEP,” the investigators note.

The prevalence of vitamin D insufficiency and deficiency was high in the population – 74.6% overall and 93.4% among ethnic minorities.

“Thus, the sample was well suited to detecting any potential benefits that may have arisen from correcting this. However, even in this subgroup, there was no evidence to support the guiding hypothesis” that vitamin D supplementation would improve outcomes in patients with early psychosis, the researchers note.

They suggest that future studies examine the association of vitamin D with brain-related outcomes based on periods of treatment longer than 6 months and administered as daily rather than bolus treatments.

“Future public health strategies should acknowledge the high prevalence of vitamin D insufficiency and deficiency in people with psychosis and consider any reasonable adjustments which may be needed to address this over and above general population guidance,” said Dr. Gaughran.

The study was funded by the Stanley Medical Research Institute and received support from the National Institute for Health Research Maudsley Biomedical Research Centre, King’s College London, and the NIHR Applied Research Collaboration South London. Dr. Gaughran reported receiving speaking honoraria from Otsuka Lundbeck outside the submitted work. A complete list of author disclosures is available with the original article.

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

Low vitamin D is common in patients with first-episode psychosis (FEP), but supplementation does not appear to improve mental or physical symptoms, new data show.

“Previous work, our own and others, has shown that people with psychosis, even soon after their first diagnosis, have low vitamin D levels, but it was not known whether supplementing with vitamin D in people with early psychosis would improve health outcomes,” study investigator Fiona Gaughran, MD, with the Institute of Psychiatry, Psychology & Neuroscience, King’s College London, told this news organization.

“While we did not demonstrate a benefit of supplementation over 6 months, these very high rates of vitamin deficiency and insufficiency may have longer-term negative health impacts which we have not measured, so raising awareness of the need to optimize vitamin D in people with psychosis is important,” said Dr. Gaughran.

The results of the randomized clinical trial were published online Dec. 28 in JAMA Network Open.

Thoughtful approach, negative result

Participants included 149 adults within 3 years of a first presentation with a functional psychotic disorder. The cohort’s mean age was 28 years, 60% were men, 44% were Black or of other racial and ethnic minority groups, and 56% were White.

Seventy-five participants were randomly assigned to receive 120,000 IU of cholecalciferol or matching placebo administered by the researchers in monthly doses with an oral syringe.

“We chose a dose of 120,000 IU monthly (equivalent to 4,000 IU daily) which was expected to safely increase vitamin D levels. The regimen was discussed with experts with lived experience, and took into account that a daily preparation would add to the significant medication load that people with psychosis already carry,” said Dr. Gaughran.

Vitamin D supplementation as administered in this study was safe and led to a significant increase in 25-hydroxyvitamin D concentrations.

However, there was no significant difference between vitamin D and placebo in the primary outcome of total Positive and Negative Syndrome Scale (PANSS) score at 6 months (mean difference, 3.57; 95% confidence interval, –1.11 to 8.25; P = .13).

There was also no apparent benefit of vitamin D supplementation on any secondary outcome, including the PANSS subscores of global function and depression or cardiometabolic risk factors.

“With respect to clinical practice, we cannot now recommend monthly treatments with 120,000 IU of cholecalciferol in FEP,” the investigators note.

The prevalence of vitamin D insufficiency and deficiency was high in the population – 74.6% overall and 93.4% among ethnic minorities.

“Thus, the sample was well suited to detecting any potential benefits that may have arisen from correcting this. However, even in this subgroup, there was no evidence to support the guiding hypothesis” that vitamin D supplementation would improve outcomes in patients with early psychosis, the researchers note.

They suggest that future studies examine the association of vitamin D with brain-related outcomes based on periods of treatment longer than 6 months and administered as daily rather than bolus treatments.

“Future public health strategies should acknowledge the high prevalence of vitamin D insufficiency and deficiency in people with psychosis and consider any reasonable adjustments which may be needed to address this over and above general population guidance,” said Dr. Gaughran.

The study was funded by the Stanley Medical Research Institute and received support from the National Institute for Health Research Maudsley Biomedical Research Centre, King’s College London, and the NIHR Applied Research Collaboration South London. Dr. Gaughran reported receiving speaking honoraria from Otsuka Lundbeck outside the submitted work. A complete list of author disclosures is available with the original article.

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

Low vitamin D is common in patients with first-episode psychosis (FEP), but supplementation does not appear to improve mental or physical symptoms, new data show.

“Previous work, our own and others, has shown that people with psychosis, even soon after their first diagnosis, have low vitamin D levels, but it was not known whether supplementing with vitamin D in people with early psychosis would improve health outcomes,” study investigator Fiona Gaughran, MD, with the Institute of Psychiatry, Psychology & Neuroscience, King’s College London, told this news organization.

“While we did not demonstrate a benefit of supplementation over 6 months, these very high rates of vitamin deficiency and insufficiency may have longer-term negative health impacts which we have not measured, so raising awareness of the need to optimize vitamin D in people with psychosis is important,” said Dr. Gaughran.

The results of the randomized clinical trial were published online Dec. 28 in JAMA Network Open.

Thoughtful approach, negative result

Participants included 149 adults within 3 years of a first presentation with a functional psychotic disorder. The cohort’s mean age was 28 years, 60% were men, 44% were Black or of other racial and ethnic minority groups, and 56% were White.

Seventy-five participants were randomly assigned to receive 120,000 IU of cholecalciferol or matching placebo administered by the researchers in monthly doses with an oral syringe.

“We chose a dose of 120,000 IU monthly (equivalent to 4,000 IU daily) which was expected to safely increase vitamin D levels. The regimen was discussed with experts with lived experience, and took into account that a daily preparation would add to the significant medication load that people with psychosis already carry,” said Dr. Gaughran.

Vitamin D supplementation as administered in this study was safe and led to a significant increase in 25-hydroxyvitamin D concentrations.

However, there was no significant difference between vitamin D and placebo in the primary outcome of total Positive and Negative Syndrome Scale (PANSS) score at 6 months (mean difference, 3.57; 95% confidence interval, –1.11 to 8.25; P = .13).

There was also no apparent benefit of vitamin D supplementation on any secondary outcome, including the PANSS subscores of global function and depression or cardiometabolic risk factors.

“With respect to clinical practice, we cannot now recommend monthly treatments with 120,000 IU of cholecalciferol in FEP,” the investigators note.

The prevalence of vitamin D insufficiency and deficiency was high in the population – 74.6% overall and 93.4% among ethnic minorities.

“Thus, the sample was well suited to detecting any potential benefits that may have arisen from correcting this. However, even in this subgroup, there was no evidence to support the guiding hypothesis” that vitamin D supplementation would improve outcomes in patients with early psychosis, the researchers note.

They suggest that future studies examine the association of vitamin D with brain-related outcomes based on periods of treatment longer than 6 months and administered as daily rather than bolus treatments.

“Future public health strategies should acknowledge the high prevalence of vitamin D insufficiency and deficiency in people with psychosis and consider any reasonable adjustments which may be needed to address this over and above general population guidance,” said Dr. Gaughran.

The study was funded by the Stanley Medical Research Institute and received support from the National Institute for Health Research Maudsley Biomedical Research Centre, King’s College London, and the NIHR Applied Research Collaboration South London. Dr. Gaughran reported receiving speaking honoraria from Otsuka Lundbeck outside the submitted work. A complete list of author disclosures is available with the original article.

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

Among women with breast cancer being treated with aromatase inhibitors (AI), supplementation with vitamin D and calcium protected against bone loss after 5 years, according to results from a prospective cohort study in Brazil. The study found no difference in bone mineral density outcomes at 5 years between women with hormone receptor–positive cancers treated with aromatase inhibitors (AIG) and triple negative or HER-2 positive patients who were treated with another therapy (CG).

Courtesy Renata Flores

About two-thirds of women with breast cancer have tumors that are positive for hormone receptors, and so are often treated with endocrine therapy such as selective estrogen receptor modulators or AI. However, there are concerns that AI treatment may lead to a loss of bone mineral density and impacts on quality of life. This loss is influenced by a range of factors, including body weight, physical activity, smoking, alcohol consumption, corticosteroid use, calcium in the diet, and circulating levels of vitamin D.

Vitamin D helps to regulate absorption of calcium and phosphorus, ensuring that their plasma concentrations are high enough for adequate bone health. But vitamin D deficiency is a common problem, even in tropical areas such as Brazil. “It is high in the general population and especially in postmenopausal breast cancer patients. Thus, vitamin D and calcium supplementation has an impact on these women’s lives,” said lead author Marcelo Antonini, MD, who presented the study (abstract P1-13-04) at the San Antonio Breast Cancer Symposium. He is a researcher at Hospital Servidor Publico Estadual in São Paulo, Brazil.

Although the findings are encouraging, more work needs to be done before it leads to a change in practice. “Larger studies must be carried out to prove this theory; however, in noncancer patients we have already well established the benefits of vitamin D and calcium supplementation,” Dr. Antonini said in an interview

The researchers examined women before the start of treatment, at 6 months, and at 5 years. Those with vitamin D levels below 30 ng/mL received 7,000 IU/day for 8 weeks, followed by a 1,000 IU/day maintenance dose. Subjects with osteopenia received a calcium supplement (500 mg calcium carbonate), and those with osteoporosis received 4 mg zoledronic acid (Zometa, Novartis).

There were 140 patients in both the AIG and CG groups. The average age was 65 years. Sixty-four percent of the AIG group and 71% of the CG group were vitamin D deficient at baseline. At 5 years, the frequencies were 17% and 16%, respectively. Both groups showed significant declines in bone mineral density in the femoral neck and femur at both 6 months and 5 years, but there was no significant difference between them. There was no significant difference between the two groups with respect to bone density loss in the spine.

The study is limited by the fact that it was conducted at a single center and had a small population size.

Another prospective observational study, published earlier this year, looked at vitamin D supplementation in 741 patients (mean age 61.9 years) being treated with aromatase inhibitors, whose baseline vitamin D levels were less 30 ng/mL. They received 16,000 IU dose of oral calcifediol every 2 weeks. At 3 months, individuals who achieved vitamin D levels of 40 ng/mL or higher were less likely to have joint pain (P < .05). At 12 months, data from 473 patients showed that for every 10-ng/mL increase in serum vitamin D at 3 months, there was a reduction in loss of bone marrow density in the lumbar spine (adjusted beta = +0.177%, P < .05), though there were no associations between vitamin D levels and BMD of the femur or total hip.

“Our results suggest that optimal levels of vitamin D are associated with a reduced risk of joint pain related to AI treatment. A target threshold (of vitamin D) levels was set at 40 ng/mL to significantly reduce the increase in joint pain. The authors noted that this threshold is well above the goal of 20 ng/mL recommended by the 2010 Institute of Medicine report.

The study did not receive external funding. Dr. Antonini has no relevant financial disclosures.

Among women with breast cancer being treated with aromatase inhibitors (AI), supplementation with vitamin D and calcium protected against bone loss after 5 years, according to results from a prospective cohort study in Brazil. The study found no difference in bone mineral density outcomes at 5 years between women with hormone receptor–positive cancers treated with aromatase inhibitors (AIG) and triple negative or HER-2 positive patients who were treated with another therapy (CG).

Courtesy Renata Flores

About two-thirds of women with breast cancer have tumors that are positive for hormone receptors, and so are often treated with endocrine therapy such as selective estrogen receptor modulators or AI. However, there are concerns that AI treatment may lead to a loss of bone mineral density and impacts on quality of life. This loss is influenced by a range of factors, including body weight, physical activity, smoking, alcohol consumption, corticosteroid use, calcium in the diet, and circulating levels of vitamin D.

Vitamin D helps to regulate absorption of calcium and phosphorus, ensuring that their plasma concentrations are high enough for adequate bone health. But vitamin D deficiency is a common problem, even in tropical areas such as Brazil. “It is high in the general population and especially in postmenopausal breast cancer patients. Thus, vitamin D and calcium supplementation has an impact on these women’s lives,” said lead author Marcelo Antonini, MD, who presented the study (abstract P1-13-04) at the San Antonio Breast Cancer Symposium. He is a researcher at Hospital Servidor Publico Estadual in São Paulo, Brazil.

Although the findings are encouraging, more work needs to be done before it leads to a change in practice. “Larger studies must be carried out to prove this theory; however, in noncancer patients we have already well established the benefits of vitamin D and calcium supplementation,” Dr. Antonini said in an interview

The researchers examined women before the start of treatment, at 6 months, and at 5 years. Those with vitamin D levels below 30 ng/mL received 7,000 IU/day for 8 weeks, followed by a 1,000 IU/day maintenance dose. Subjects with osteopenia received a calcium supplement (500 mg calcium carbonate), and those with osteoporosis received 4 mg zoledronic acid (Zometa, Novartis).

There were 140 patients in both the AIG and CG groups. The average age was 65 years. Sixty-four percent of the AIG group and 71% of the CG group were vitamin D deficient at baseline. At 5 years, the frequencies were 17% and 16%, respectively. Both groups showed significant declines in bone mineral density in the femoral neck and femur at both 6 months and 5 years, but there was no significant difference between them. There was no significant difference between the two groups with respect to bone density loss in the spine.

The study is limited by the fact that it was conducted at a single center and had a small population size.

Another prospective observational study, published earlier this year, looked at vitamin D supplementation in 741 patients (mean age 61.9 years) being treated with aromatase inhibitors, whose baseline vitamin D levels were less 30 ng/mL. They received 16,000 IU dose of oral calcifediol every 2 weeks. At 3 months, individuals who achieved vitamin D levels of 40 ng/mL or higher were less likely to have joint pain (P < .05). At 12 months, data from 473 patients showed that for every 10-ng/mL increase in serum vitamin D at 3 months, there was a reduction in loss of bone marrow density in the lumbar spine (adjusted beta = +0.177%, P < .05), though there were no associations between vitamin D levels and BMD of the femur or total hip.

“Our results suggest that optimal levels of vitamin D are associated with a reduced risk of joint pain related to AI treatment. A target threshold (of vitamin D) levels was set at 40 ng/mL to significantly reduce the increase in joint pain. The authors noted that this threshold is well above the goal of 20 ng/mL recommended by the 2010 Institute of Medicine report.

The study did not receive external funding. Dr. Antonini has no relevant financial disclosures.

Among women with breast cancer being treated with aromatase inhibitors (AI), supplementation with vitamin D and calcium protected against bone loss after 5 years, according to results from a prospective cohort study in Brazil. The study found no difference in bone mineral density outcomes at 5 years between women with hormone receptor–positive cancers treated with aromatase inhibitors (AIG) and triple negative or HER-2 positive patients who were treated with another therapy (CG).

Courtesy Renata Flores

About two-thirds of women with breast cancer have tumors that are positive for hormone receptors, and so are often treated with endocrine therapy such as selective estrogen receptor modulators or AI. However, there are concerns that AI treatment may lead to a loss of bone mineral density and impacts on quality of life. This loss is influenced by a range of factors, including body weight, physical activity, smoking, alcohol consumption, corticosteroid use, calcium in the diet, and circulating levels of vitamin D.

Vitamin D helps to regulate absorption of calcium and phosphorus, ensuring that their plasma concentrations are high enough for adequate bone health. But vitamin D deficiency is a common problem, even in tropical areas such as Brazil. “It is high in the general population and especially in postmenopausal breast cancer patients. Thus, vitamin D and calcium supplementation has an impact on these women’s lives,” said lead author Marcelo Antonini, MD, who presented the study (abstract P1-13-04) at the San Antonio Breast Cancer Symposium. He is a researcher at Hospital Servidor Publico Estadual in São Paulo, Brazil.

Although the findings are encouraging, more work needs to be done before it leads to a change in practice. “Larger studies must be carried out to prove this theory; however, in noncancer patients we have already well established the benefits of vitamin D and calcium supplementation,” Dr. Antonini said in an interview

The researchers examined women before the start of treatment, at 6 months, and at 5 years. Those with vitamin D levels below 30 ng/mL received 7,000 IU/day for 8 weeks, followed by a 1,000 IU/day maintenance dose. Subjects with osteopenia received a calcium supplement (500 mg calcium carbonate), and those with osteoporosis received 4 mg zoledronic acid (Zometa, Novartis).

There were 140 patients in both the AIG and CG groups. The average age was 65 years. Sixty-four percent of the AIG group and 71% of the CG group were vitamin D deficient at baseline. At 5 years, the frequencies were 17% and 16%, respectively. Both groups showed significant declines in bone mineral density in the femoral neck and femur at both 6 months and 5 years, but there was no significant difference between them. There was no significant difference between the two groups with respect to bone density loss in the spine.

The study is limited by the fact that it was conducted at a single center and had a small population size.

Another prospective observational study, published earlier this year, looked at vitamin D supplementation in 741 patients (mean age 61.9 years) being treated with aromatase inhibitors, whose baseline vitamin D levels were less 30 ng/mL. They received 16,000 IU dose of oral calcifediol every 2 weeks. At 3 months, individuals who achieved vitamin D levels of 40 ng/mL or higher were less likely to have joint pain (P < .05). At 12 months, data from 473 patients showed that for every 10-ng/mL increase in serum vitamin D at 3 months, there was a reduction in loss of bone marrow density in the lumbar spine (adjusted beta = +0.177%, P < .05), though there were no associations between vitamin D levels and BMD of the femur or total hip.

“Our results suggest that optimal levels of vitamin D are associated with a reduced risk of joint pain related to AI treatment. A target threshold (of vitamin D) levels was set at 40 ng/mL to significantly reduce the increase in joint pain. The authors noted that this threshold is well above the goal of 20 ng/mL recommended by the 2010 Institute of Medicine report.

The study did not receive external funding. Dr. Antonini has no relevant financial disclosures.

Recently, the National Osteoporosis Foundation (NOF) changed its name to the Bone Health and Osteoporosis Foundation (BHOF). Several years ago, in 2016 at my urging, this column was renamed from “Update on osteoporosis” to “Update on bone health.” I believe we were on the leading edge of this movement. As expressed in last year’s Update, our patients’ bone health must be emphasized more than it has been in the past.¹

Consider that localized breast cancer carries a 5-year survival rate of 99%.² Most of my patients are keenly aware that periodic competent breast imaging is the key to the earliest possible diagnosis. By contrast, in this country a hip fracture carries a mortality in the first year of 21%!³ Furthermore, approximately one-third of women who fracture their hip do not have osteoporosis.⁴ While the risk of hip fracture is greatest in women with osteoporosis, it is not absent in those without the condition. Finally, the role of muscle mass, strength, and performance in bone health is a rapidly emerging topic and one that constitutes the core of this year’s Update.

Muscle mass and strength play key role in bone health

de Villiers TJ, Goldstein SR. Update on bone health: the International Menopause Society white paper 2021. Climacteric. 2021;24:498-504. doi:10.1080/13697137.2021.1950967.

Recently, de Villiers and Goldstein offered an overview of osteoporosis.⁵ What is worthy of reporting here is the role of muscle in bone health.

The bone-muscle relationship

Most clinicians know that osteoporosis and osteopenia are well-defined conditions with known risks associated with fracture. According to a review of PubMed, the first article with the keyword “osteoporosis” was published in 1894; through May 2020, 93,335 articles used that keyword. “Osteoporosis” is derived from the Greek osteon (bone) and poros (little hole). Thus, osteoporosis means “porous bone.”

Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass, strength, and function, and the condition is associated with a risk of adverse outcomes that include physical disabilities, poor quality of life, and death.^6,7 “Sarcopenia” has its roots in the Greek words sarx (flesh) and penia (loss), and the term was coined in 1989.⁸ A PubMed review that included “sarcopenia” as the keyword revealed that the first article was published in 1993, with 12,068 articles published through May 2020.

Notably, muscle accounts for about 60% of the body’s protein. Muscle mass decreases with age, but younger patients with malnutrition, cachexia, or inflammatory diseases are also prone to decreased muscle mass. While osteoporosis has a well-accepted definition based on dual-energy x-ray absorptiometry (DXA) measurements, sarcopenia has no universally accepted definition, consensus diagnostic criteria, or treatment guidelines. In 2016, however, the International Classification of Diseases, Tenth Revision, Clinical Modification (CD-10-CM) finally recognized sarcopenia as a disease entity.

Currently, the most widely accepted definition comes from the European Working Group on Sarcopenia in Older People, which labeled presarcopenia as low muscle mass without impact on muscle strength or performance; sarcopenia as low muscle mass with either low muscle strength or low physical performance; and severe sarcopenia has all 3 criteria being present.⁹

When osteosarcopenia (osteoporosis or osteopenia combined with sarcopenia) exists, it can result in a threefold increase in risk of falls and a fourfold increase in fracture risk compared with women who have osteopenia or osteoporosis alone.¹⁰

Continue to: Denosumab decreased falls risk, improved sarcopenia measures vs comparator antiresorptives...

Denosumab decreased falls risk, improved sarcopenia measures vs comparator antiresorptives

El Miedany Y, El Gaafary M, Toth M, et al; Egyptian Academy of Bone Health, Metabolic Bone Diseases. Is there a potential dual effect of denosumab for treatment of osteoporosis and sarcopenia? Clin Rheumatol. 2021;40:4225-4232. doi: 10.1007/s10067-021 -05757-w.

Osteosarcopenia, the combination of osteoporosis or osteopenia with sarcopenia, has been shown to increase the overall rate of falls and fracture when compared with fall and fracture rates in women with osteopenia or osteoporosis alone.¹⁰ A study by El Miedany and colleagues examined whether denosumab treatment had a possible dual therapeutic effect on osteoporosis and sarcopenia.¹¹

Study details

The investigators looked at 135 patients diagnosed with postmenopausal osteoporosis and who were prescribed denosumab and compared them with a control group of 272 patients stratified into 2 subgroups: 136 were prescribed alendronate and 136 were prescribed zoledronate.

Assessments were performed for all participants for BMD (DXA), fall risk (falls risk assessment score [FRAS]), fracture risk (FRAX assessment tool), and sarcopenia measures. Reassessments were conducted after 5 years of denosumab or alendronate therapy, 3 years of zoledronate therapy, and 1 year after stopping the osteoporosis therapy.

The FRAS uses the clinical variables of history of falls in the last 12 months, impaired sight, weak hand grip, history of loss of balance in the last 12 months, and slowing of the walking speed/change in gait to yield a percent chance of sustaining a fall.¹² Sarcopenic measures include grip strength, timed up and go (TUG) mobility test, and gait speed. There were no significant demographic differences between the 3 groups.

Denosumab reduced risk of falls and positively affected muscle strength

On completion of the 5-year denosumab therapy, falls risk was significantly decreased (P = .001) and significant improvements were seen in all sarcopenia measures (P = .01). One year after denosumab was discontinued, a significant worsening of both falls risk and sarcopenia measures (P = .01) occurred. This was in contrast to results in both control groups (alendronate and zoledronate), in which there was an improvement, although less robust in gait speed and the TUG test (P = .05) but no improvement in risk of falls. Thus, the results of this study showed that denosumab not only improved bone mass but also reduced falls risk.

Compared with bisphosphonates, denosumab showed the highest significant positive effect on both physical performance and skeletal muscle strength. This is evidenced by improvement of the gait speed, TUG test, and 4-m walk test (P<.001) in the denosumab group versus in the alendronate and zoledronate group (P<.05).

These results agree with the outcomes of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis 6 months) trial, which revealed that not only did denosumab treatment reduce the risk of vertebral, nonvertebral, and hip fracture over 36 months, but also that the denosumab-treated group had fewer falls (4.5%) compared with the other groups (5.7%) (P = .02).¹³

Continue to: Estrogen’s role in bone health and its therapeutic potential in osteosarcopenia...

Estrogen’s role in bone health and its therapeutic potential in osteosarcopenia

Mandelli A, Tacconi E, Levinger I, et al. The role of estrogens in osteosarcopenia: from biology to potential dual therapeutic effects. Climacteric. 2021;1-7. doi: 10.1080/13697137.2021.1965118.

Osteosarcopenia is a particular term used to describe the coexistence of 2 pathologies, osteopenia/ osteoporosis and sarcopenia.¹⁴ Sarcopenia is characterized by a loss of muscle mass, strength, and performance. Numerous studies indicate that higher lean body mass is related to increased BMD and reduced fracture risk, especially in postmenopausal women.¹⁵

Menopause, muscle, and estrogen’s physiologic effects

Estrogens play a critical role in maintaining bone and muscle mass in women. Women experience a decline in musculoskeletal quantity and quality at the onset of menopause.¹⁶ Muscle mass and strength decrease rapidly after menopause, which suggests that degradation of muscle protein begins to exert a more significant effect due to a decrease in protein synthesis. Indeed, a reduced response to anabolic stimuli has been shown in postmenopausal women.¹⁷ Normalization of the protein synthesis response after restoring estrogen levels with estrogen therapy supports this hypothesis.¹⁸

In a meta-analysis to identify the role of estrogen therapy on muscle strength, the authors concluded that estrogens benefit muscle strength not by increasing the skeletal mass but by improving muscle quality and its ability to generate force.¹⁹ In addition, however, it has been demonstrated that exercise prevents and delays the onset of osteosarcopenia.²⁰

When should bone mass be measured in premenopausal women?

Conradie M, de Villiers T. Premenopausal osteoporosis. Climacteric. 2021:1-14. doi: 10.1080/13697137 .2021.1926974.

Most women’s clinicians are somewhat well acquainted with the increasing importance of preventing, diagnosing, and treating postmenopausal osteoporosis, which predisposes to fragility fracture and the morbidity and even mortality that brings. Increasingly, some younger women are asking for and receiving both bone mass measurements that may be inappropriately ordered and/or wrongly interpreted. Conradie and de Villiers provided an overview of premenopausal osteoporosis, containing important facts that all clinicians who care for women should be aware of.²¹

Indications for testing

BMD testing is only indicated in younger women in settings in which the result may influence management decisions, such as:

• a history of fragility fracture
• diseases associated with low bone mass, such as anorexia nervosa, hypogonadism, hyperparathyroidism, hyperthyroidism, celiac disease, irritable bowel disease, rheumatoid arthritis, lupus, renal disease, Marfan syndrome
• medications, such as glucocorticoids, aromatase inhibitors, premenopausal tamoxifen, excess thyroid hormone replacement, progesterone contraception
• excessive alcohol consumption, heavy smoking, vitamin D deficiency, calcium deficiency, occasionally veganism or vegetarianism.

BMD interpretation in premenopausal women does not use the T-scores developed for postmenopausal women in which standard deviations (SD) from the mean for a young reference population are employed. In that population, the normal range is up to -1.0 SD; osteopenia > -1.0 < -2.5 SD; and osteoporosis > -2.5 SD. Instead, in premenopausal patients, Z-scores, which compare the measured bone mass to an age- and gender-matched cohort, are employed. Z-scores > 2 SD below the matched population should be used rather than the T-scores that are already familiar to most clinicians.

Up to 90% of these premenopausal women with such skeletal fragility will display the secondary causes described above. ●

Recently, the National Osteoporosis Foundation (NOF) changed its name to the Bone Health and Osteoporosis Foundation (BHOF). Several years ago, in 2016 at my urging, this column was renamed from “Update on osteoporosis” to “Update on bone health.” I believe we were on the leading edge of this movement. As expressed in last year’s Update, our patients’ bone health must be emphasized more than it has been in the past.¹

Consider that localized breast cancer carries a 5-year survival rate of 99%.² Most of my patients are keenly aware that periodic competent breast imaging is the key to the earliest possible diagnosis. By contrast, in this country a hip fracture carries a mortality in the first year of 21%!³ Furthermore, approximately one-third of women who fracture their hip do not have osteoporosis.⁴ While the risk of hip fracture is greatest in women with osteoporosis, it is not absent in those without the condition. Finally, the role of muscle mass, strength, and performance in bone health is a rapidly emerging topic and one that constitutes the core of this year’s Update.

Muscle mass and strength play key role in bone health

de Villiers TJ, Goldstein SR. Update on bone health: the International Menopause Society white paper 2021. Climacteric. 2021;24:498-504. doi:10.1080/13697137.2021.1950967.

Recently, de Villiers and Goldstein offered an overview of osteoporosis.⁵ What is worthy of reporting here is the role of muscle in bone health.

The bone-muscle relationship

Most clinicians know that osteoporosis and osteopenia are well-defined conditions with known risks associated with fracture. According to a review of PubMed, the first article with the keyword “osteoporosis” was published in 1894; through May 2020, 93,335 articles used that keyword. “Osteoporosis” is derived from the Greek osteon (bone) and poros (little hole). Thus, osteoporosis means “porous bone.”

Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass, strength, and function, and the condition is associated with a risk of adverse outcomes that include physical disabilities, poor quality of life, and death.^6,7 “Sarcopenia” has its roots in the Greek words sarx (flesh) and penia (loss), and the term was coined in 1989.⁸ A PubMed review that included “sarcopenia” as the keyword revealed that the first article was published in 1993, with 12,068 articles published through May 2020.

Notably, muscle accounts for about 60% of the body’s protein. Muscle mass decreases with age, but younger patients with malnutrition, cachexia, or inflammatory diseases are also prone to decreased muscle mass. While osteoporosis has a well-accepted definition based on dual-energy x-ray absorptiometry (DXA) measurements, sarcopenia has no universally accepted definition, consensus diagnostic criteria, or treatment guidelines. In 2016, however, the International Classification of Diseases, Tenth Revision, Clinical Modification (CD-10-CM) finally recognized sarcopenia as a disease entity.

Currently, the most widely accepted definition comes from the European Working Group on Sarcopenia in Older People, which labeled presarcopenia as low muscle mass without impact on muscle strength or performance; sarcopenia as low muscle mass with either low muscle strength or low physical performance; and severe sarcopenia has all 3 criteria being present.⁹

When osteosarcopenia (osteoporosis or osteopenia combined with sarcopenia) exists, it can result in a threefold increase in risk of falls and a fourfold increase in fracture risk compared with women who have osteopenia or osteoporosis alone.¹⁰

Continue to: Denosumab decreased falls risk, improved sarcopenia measures vs comparator antiresorptives...

Denosumab decreased falls risk, improved sarcopenia measures vs comparator antiresorptives

El Miedany Y, El Gaafary M, Toth M, et al; Egyptian Academy of Bone Health, Metabolic Bone Diseases. Is there a potential dual effect of denosumab for treatment of osteoporosis and sarcopenia? Clin Rheumatol. 2021;40:4225-4232. doi: 10.1007/s10067-021 -05757-w.

Osteosarcopenia, the combination of osteoporosis or osteopenia with sarcopenia, has been shown to increase the overall rate of falls and fracture when compared with fall and fracture rates in women with osteopenia or osteoporosis alone.¹⁰ A study by El Miedany and colleagues examined whether denosumab treatment had a possible dual therapeutic effect on osteoporosis and sarcopenia.¹¹

Study details

The investigators looked at 135 patients diagnosed with postmenopausal osteoporosis and who were prescribed denosumab and compared them with a control group of 272 patients stratified into 2 subgroups: 136 were prescribed alendronate and 136 were prescribed zoledronate.

Assessments were performed for all participants for BMD (DXA), fall risk (falls risk assessment score [FRAS]), fracture risk (FRAX assessment tool), and sarcopenia measures. Reassessments were conducted after 5 years of denosumab or alendronate therapy, 3 years of zoledronate therapy, and 1 year after stopping the osteoporosis therapy.

The FRAS uses the clinical variables of history of falls in the last 12 months, impaired sight, weak hand grip, history of loss of balance in the last 12 months, and slowing of the walking speed/change in gait to yield a percent chance of sustaining a fall.¹² Sarcopenic measures include grip strength, timed up and go (TUG) mobility test, and gait speed. There were no significant demographic differences between the 3 groups.

Denosumab reduced risk of falls and positively affected muscle strength

On completion of the 5-year denosumab therapy, falls risk was significantly decreased (P = .001) and significant improvements were seen in all sarcopenia measures (P = .01). One year after denosumab was discontinued, a significant worsening of both falls risk and sarcopenia measures (P = .01) occurred. This was in contrast to results in both control groups (alendronate and zoledronate), in which there was an improvement, although less robust in gait speed and the TUG test (P = .05) but no improvement in risk of falls. Thus, the results of this study showed that denosumab not only improved bone mass but also reduced falls risk.

Compared with bisphosphonates, denosumab showed the highest significant positive effect on both physical performance and skeletal muscle strength. This is evidenced by improvement of the gait speed, TUG test, and 4-m walk test (P<.001) in the denosumab group versus in the alendronate and zoledronate group (P<.05).

These results agree with the outcomes of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis 6 months) trial, which revealed that not only did denosumab treatment reduce the risk of vertebral, nonvertebral, and hip fracture over 36 months, but also that the denosumab-treated group had fewer falls (4.5%) compared with the other groups (5.7%) (P = .02).¹³

Continue to: Estrogen’s role in bone health and its therapeutic potential in osteosarcopenia...

Estrogen’s role in bone health and its therapeutic potential in osteosarcopenia

Mandelli A, Tacconi E, Levinger I, et al. The role of estrogens in osteosarcopenia: from biology to potential dual therapeutic effects. Climacteric. 2021;1-7. doi: 10.1080/13697137.2021.1965118.

Osteosarcopenia is a particular term used to describe the coexistence of 2 pathologies, osteopenia/ osteoporosis and sarcopenia.¹⁴ Sarcopenia is characterized by a loss of muscle mass, strength, and performance. Numerous studies indicate that higher lean body mass is related to increased BMD and reduced fracture risk, especially in postmenopausal women.¹⁵

Menopause, muscle, and estrogen’s physiologic effects

Estrogens play a critical role in maintaining bone and muscle mass in women. Women experience a decline in musculoskeletal quantity and quality at the onset of menopause.¹⁶ Muscle mass and strength decrease rapidly after menopause, which suggests that degradation of muscle protein begins to exert a more significant effect due to a decrease in protein synthesis. Indeed, a reduced response to anabolic stimuli has been shown in postmenopausal women.¹⁷ Normalization of the protein synthesis response after restoring estrogen levels with estrogen therapy supports this hypothesis.¹⁸

In a meta-analysis to identify the role of estrogen therapy on muscle strength, the authors concluded that estrogens benefit muscle strength not by increasing the skeletal mass but by improving muscle quality and its ability to generate force.¹⁹ In addition, however, it has been demonstrated that exercise prevents and delays the onset of osteosarcopenia.²⁰

When should bone mass be measured in premenopausal women?

Conradie M, de Villiers T. Premenopausal osteoporosis. Climacteric. 2021:1-14. doi: 10.1080/13697137 .2021.1926974.

Most women’s clinicians are somewhat well acquainted with the increasing importance of preventing, diagnosing, and treating postmenopausal osteoporosis, which predisposes to fragility fracture and the morbidity and even mortality that brings. Increasingly, some younger women are asking for and receiving both bone mass measurements that may be inappropriately ordered and/or wrongly interpreted. Conradie and de Villiers provided an overview of premenopausal osteoporosis, containing important facts that all clinicians who care for women should be aware of.²¹

Indications for testing

BMD testing is only indicated in younger women in settings in which the result may influence management decisions, such as:

• a history of fragility fracture
• diseases associated with low bone mass, such as anorexia nervosa, hypogonadism, hyperparathyroidism, hyperthyroidism, celiac disease, irritable bowel disease, rheumatoid arthritis, lupus, renal disease, Marfan syndrome
• medications, such as glucocorticoids, aromatase inhibitors, premenopausal tamoxifen, excess thyroid hormone replacement, progesterone contraception
• excessive alcohol consumption, heavy smoking, vitamin D deficiency, calcium deficiency, occasionally veganism or vegetarianism.

BMD interpretation in premenopausal women does not use the T-scores developed for postmenopausal women in which standard deviations (SD) from the mean for a young reference population are employed. In that population, the normal range is up to -1.0 SD; osteopenia > -1.0 < -2.5 SD; and osteoporosis > -2.5 SD. Instead, in premenopausal patients, Z-scores, which compare the measured bone mass to an age- and gender-matched cohort, are employed. Z-scores > 2 SD below the matched population should be used rather than the T-scores that are already familiar to most clinicians.

Up to 90% of these premenopausal women with such skeletal fragility will display the secondary causes described above. ●

Recently, the National Osteoporosis Foundation (NOF) changed its name to the Bone Health and Osteoporosis Foundation (BHOF). Several years ago, in 2016 at my urging, this column was renamed from “Update on osteoporosis” to “Update on bone health.” I believe we were on the leading edge of this movement. As expressed in last year’s Update, our patients’ bone health must be emphasized more than it has been in the past.¹

Consider that localized breast cancer carries a 5-year survival rate of 99%.² Most of my patients are keenly aware that periodic competent breast imaging is the key to the earliest possible diagnosis. By contrast, in this country a hip fracture carries a mortality in the first year of 21%!³ Furthermore, approximately one-third of women who fracture their hip do not have osteoporosis.⁴ While the risk of hip fracture is greatest in women with osteoporosis, it is not absent in those without the condition. Finally, the role of muscle mass, strength, and performance in bone health is a rapidly emerging topic and one that constitutes the core of this year’s Update.

Muscle mass and strength play key role in bone health

de Villiers TJ, Goldstein SR. Update on bone health: the International Menopause Society white paper 2021. Climacteric. 2021;24:498-504. doi:10.1080/13697137.2021.1950967.

Recently, de Villiers and Goldstein offered an overview of osteoporosis.⁵ What is worthy of reporting here is the role of muscle in bone health.

The bone-muscle relationship

Most clinicians know that osteoporosis and osteopenia are well-defined conditions with known risks associated with fracture. According to a review of PubMed, the first article with the keyword “osteoporosis” was published in 1894; through May 2020, 93,335 articles used that keyword. “Osteoporosis” is derived from the Greek osteon (bone) and poros (little hole). Thus, osteoporosis means “porous bone.”

Sarcopenia is characterized by progressive and generalized loss of skeletal muscle mass, strength, and function, and the condition is associated with a risk of adverse outcomes that include physical disabilities, poor quality of life, and death.^6,7 “Sarcopenia” has its roots in the Greek words sarx (flesh) and penia (loss), and the term was coined in 1989.⁸ A PubMed review that included “sarcopenia” as the keyword revealed that the first article was published in 1993, with 12,068 articles published through May 2020.

Notably, muscle accounts for about 60% of the body’s protein. Muscle mass decreases with age, but younger patients with malnutrition, cachexia, or inflammatory diseases are also prone to decreased muscle mass. While osteoporosis has a well-accepted definition based on dual-energy x-ray absorptiometry (DXA) measurements, sarcopenia has no universally accepted definition, consensus diagnostic criteria, or treatment guidelines. In 2016, however, the International Classification of Diseases, Tenth Revision, Clinical Modification (CD-10-CM) finally recognized sarcopenia as a disease entity.

Currently, the most widely accepted definition comes from the European Working Group on Sarcopenia in Older People, which labeled presarcopenia as low muscle mass without impact on muscle strength or performance; sarcopenia as low muscle mass with either low muscle strength or low physical performance; and severe sarcopenia has all 3 criteria being present.⁹

When osteosarcopenia (osteoporosis or osteopenia combined with sarcopenia) exists, it can result in a threefold increase in risk of falls and a fourfold increase in fracture risk compared with women who have osteopenia or osteoporosis alone.¹⁰

Continue to: Denosumab decreased falls risk, improved sarcopenia measures vs comparator antiresorptives...

Denosumab decreased falls risk, improved sarcopenia measures vs comparator antiresorptives

El Miedany Y, El Gaafary M, Toth M, et al; Egyptian Academy of Bone Health, Metabolic Bone Diseases. Is there a potential dual effect of denosumab for treatment of osteoporosis and sarcopenia? Clin Rheumatol. 2021;40:4225-4232. doi: 10.1007/s10067-021 -05757-w.

Osteosarcopenia, the combination of osteoporosis or osteopenia with sarcopenia, has been shown to increase the overall rate of falls and fracture when compared with fall and fracture rates in women with osteopenia or osteoporosis alone.¹⁰ A study by El Miedany and colleagues examined whether denosumab treatment had a possible dual therapeutic effect on osteoporosis and sarcopenia.¹¹

Study details

The investigators looked at 135 patients diagnosed with postmenopausal osteoporosis and who were prescribed denosumab and compared them with a control group of 272 patients stratified into 2 subgroups: 136 were prescribed alendronate and 136 were prescribed zoledronate.

Assessments were performed for all participants for BMD (DXA), fall risk (falls risk assessment score [FRAS]), fracture risk (FRAX assessment tool), and sarcopenia measures. Reassessments were conducted after 5 years of denosumab or alendronate therapy, 3 years of zoledronate therapy, and 1 year after stopping the osteoporosis therapy.

The FRAS uses the clinical variables of history of falls in the last 12 months, impaired sight, weak hand grip, history of loss of balance in the last 12 months, and slowing of the walking speed/change in gait to yield a percent chance of sustaining a fall.¹² Sarcopenic measures include grip strength, timed up and go (TUG) mobility test, and gait speed. There were no significant demographic differences between the 3 groups.

Denosumab reduced risk of falls and positively affected muscle strength

On completion of the 5-year denosumab therapy, falls risk was significantly decreased (P = .001) and significant improvements were seen in all sarcopenia measures (P = .01). One year after denosumab was discontinued, a significant worsening of both falls risk and sarcopenia measures (P = .01) occurred. This was in contrast to results in both control groups (alendronate and zoledronate), in which there was an improvement, although less robust in gait speed and the TUG test (P = .05) but no improvement in risk of falls. Thus, the results of this study showed that denosumab not only improved bone mass but also reduced falls risk.

Compared with bisphosphonates, denosumab showed the highest significant positive effect on both physical performance and skeletal muscle strength. This is evidenced by improvement of the gait speed, TUG test, and 4-m walk test (P<.001) in the denosumab group versus in the alendronate and zoledronate group (P<.05).

These results agree with the outcomes of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis 6 months) trial, which revealed that not only did denosumab treatment reduce the risk of vertebral, nonvertebral, and hip fracture over 36 months, but also that the denosumab-treated group had fewer falls (4.5%) compared with the other groups (5.7%) (P = .02).¹³

Continue to: Estrogen’s role in bone health and its therapeutic potential in osteosarcopenia...

Estrogen’s role in bone health and its therapeutic potential in osteosarcopenia

Mandelli A, Tacconi E, Levinger I, et al. The role of estrogens in osteosarcopenia: from biology to potential dual therapeutic effects. Climacteric. 2021;1-7. doi: 10.1080/13697137.2021.1965118.

Osteosarcopenia is a particular term used to describe the coexistence of 2 pathologies, osteopenia/ osteoporosis and sarcopenia.¹⁴ Sarcopenia is characterized by a loss of muscle mass, strength, and performance. Numerous studies indicate that higher lean body mass is related to increased BMD and reduced fracture risk, especially in postmenopausal women.¹⁵

Menopause, muscle, and estrogen’s physiologic effects

Estrogens play a critical role in maintaining bone and muscle mass in women. Women experience a decline in musculoskeletal quantity and quality at the onset of menopause.¹⁶ Muscle mass and strength decrease rapidly after menopause, which suggests that degradation of muscle protein begins to exert a more significant effect due to a decrease in protein synthesis. Indeed, a reduced response to anabolic stimuli has been shown in postmenopausal women.¹⁷ Normalization of the protein synthesis response after restoring estrogen levels with estrogen therapy supports this hypothesis.¹⁸

In a meta-analysis to identify the role of estrogen therapy on muscle strength, the authors concluded that estrogens benefit muscle strength not by increasing the skeletal mass but by improving muscle quality and its ability to generate force.¹⁹ In addition, however, it has been demonstrated that exercise prevents and delays the onset of osteosarcopenia.²⁰

When should bone mass be measured in premenopausal women?

Conradie M, de Villiers T. Premenopausal osteoporosis. Climacteric. 2021:1-14. doi: 10.1080/13697137 .2021.1926974.

Most women’s clinicians are somewhat well acquainted with the increasing importance of preventing, diagnosing, and treating postmenopausal osteoporosis, which predisposes to fragility fracture and the morbidity and even mortality that brings. Increasingly, some younger women are asking for and receiving both bone mass measurements that may be inappropriately ordered and/or wrongly interpreted. Conradie and de Villiers provided an overview of premenopausal osteoporosis, containing important facts that all clinicians who care for women should be aware of.²¹

Indications for testing

BMD testing is only indicated in younger women in settings in which the result may influence management decisions, such as:

• a history of fragility fracture
• diseases associated with low bone mass, such as anorexia nervosa, hypogonadism, hyperparathyroidism, hyperthyroidism, celiac disease, irritable bowel disease, rheumatoid arthritis, lupus, renal disease, Marfan syndrome
• medications, such as glucocorticoids, aromatase inhibitors, premenopausal tamoxifen, excess thyroid hormone replacement, progesterone contraception
• excessive alcohol consumption, heavy smoking, vitamin D deficiency, calcium deficiency, occasionally veganism or vegetarianism.

BMD interpretation in premenopausal women does not use the T-scores developed for postmenopausal women in which standard deviations (SD) from the mean for a young reference population are employed. In that population, the normal range is up to -1.0 SD; osteopenia > -1.0 < -2.5 SD; and osteoporosis > -2.5 SD. Instead, in premenopausal patients, Z-scores, which compare the measured bone mass to an age- and gender-matched cohort, are employed. Z-scores > 2 SD below the matched population should be used rather than the T-scores that are already familiar to most clinicians.

Up to 90% of these premenopausal women with such skeletal fragility will display the secondary causes described above. ●

Women with a history of stage III to stage IV breast cancer had significantly more pathologic vertebral fractures compared to those with stage I and stage II disease, based on data from approximately 5,000 adult women.

Breast cancer remains associated with increased fracture risk in part because of estrogen deficiency, aromatase inhibitors, frailty, and skeletal metastases, wrote Joan C. Lo, MD, of Kaiser Permanente Northern California, Oakland, and colleagues. Fractures associated with these factors have been studied, but many of the existing epidemiologic studies lack detail on fractures related to cancer, they noted. The researchers examined the association between pathologic fractures and major osteoporotic fractures in women with invasive breast cancer who received endocrine therapy.

In a study published in JAMA Network Open (2021 Nov 18. doi: 10.1001/jamanetworkopen.2021.33861), the researchers reviewed data from 5,010 women enrolled in the Pathways Study (3,312 women) or Research Program on Genes, Environment, and Health (RPGEH) study (1,698 women) with newly diagnosed invasive breast cancer who received endocrine therapy. The women were followed for up to 10 years for incident fracture, with a median follow-up period of 6.7 years.

The average age of the women was 60.2 years; 73.3% were non-Hispanic White, 4.9% were Black, 9.4% were Hispanic, and 1.6% were women whose ethnicity was unknown. Approximately 90% of the women were at stage I to stage II at initial diagnosis.

Overall, 340 (6.8%) had incident fractures during the follow-up period. The incident fractures included 46 hip, 104 vertebral, 78 humerus, and 137 wrist fractures. Significantly more women with hip fracture (43.5%) were age 80 years or older, compared with less than 25% of women with vertebral fractures (22.1%), humerus (19.2%), or wrist fracture (15.3%).

Pathologic fractures accounted for 22 of 104 incident vertebral fractures (21.2%) and fewer than 5 of 46 incident hip fractures (8.7%); few wrist and humerus fractures were pathologic. According to tumor stage, 15 of 87 (17.2%) vertebral fractures in women with initial stage I and II were pathologic, compared to 7 of 17 (41.2%) in women with initial stage III to stage IV breast cancer (P < .05).

The results emphasized the need to consider vertebral fracture risk in women with breast cancer, notably advanced stage cancer, as approximately one-third of the incident vertebral fractures in this subset of patients was deemed cancer-related, the researchers noted.

“As the axial skeleton is a common site for breast cancer metastasis and vertebrae a common site for pathologic fracture, primary care physicians should consider the possibility of pathologic fracture in women with higher risk based on advanced-stage cancer history,” the researchers wrote.

The study findings were limited by several factors, including the lack of data on fracture risk factors, treatment, and chemotherapy, and the inclusion only of clinically diagnosed fractures and not asymptomatic vertebral fractures, the researchers noted. However, the results were strengthened by the large sample size and comprehensive fracture assessment, they said. Additional studies to examine nonpathologic fracture risk according to breast cancer treatment, such as the use of aromatase inhibitors versus cytotoxic chemotherapy, may inform which women would benefit from more aggressive osteoporotic fracture prevention, they concluded.
 

Findings inform shared decision-making

“This study highlights the apparent association between an initial diagnosis of stage III or IV breast cancer and an increased risk for pathologic vertebral fracture,” said Constance Bohon, MD, a gynecologist in private practice in Washington, D.C., in an interview. “Most likely this finding is secondary to breast cancer metastases,” Dr. Bohon noted. However, she questioned whether there is a difference in fracture rates between women who received only aromatase inhibitors, those who received tamoxifen, and those who received both treatments.

“Additional data to determine the age of menopause, exercise frequency, current weight, and family history of osteoporosis may serve to identify those at highest risk for pathologic vertebral fracture,” said Dr. Bohon. “Until further data are available, clinicians should review this study and counsel their patients regarding options to potentially mitigate their apparent increased risk for pathologic vertebral fracture,” she emphasized.

The study was supported by the National Cancer Institute, National Institutes of Health, and the Research Program on Genes, Environment, and Health of Kaiser Permanente Northern California. The researchers had no financial conflicts to disclose. Dr. Bohon had no financial conflicts to disclose but serves on the Editorial Advisory Board of Ob.Gyn. News.

obnews@mdedge.com

Women with a history of stage III to stage IV breast cancer had significantly more pathologic vertebral fractures compared to those with stage I and stage II disease, based on data from approximately 5,000 adult women.

Breast cancer remains associated with increased fracture risk in part because of estrogen deficiency, aromatase inhibitors, frailty, and skeletal metastases, wrote Joan C. Lo, MD, of Kaiser Permanente Northern California, Oakland, and colleagues. Fractures associated with these factors have been studied, but many of the existing epidemiologic studies lack detail on fractures related to cancer, they noted. The researchers examined the association between pathologic fractures and major osteoporotic fractures in women with invasive breast cancer who received endocrine therapy.

In a study published in JAMA Network Open (2021 Nov 18. doi: 10.1001/jamanetworkopen.2021.33861), the researchers reviewed data from 5,010 women enrolled in the Pathways Study (3,312 women) or Research Program on Genes, Environment, and Health (RPGEH) study (1,698 women) with newly diagnosed invasive breast cancer who received endocrine therapy. The women were followed for up to 10 years for incident fracture, with a median follow-up period of 6.7 years.

The average age of the women was 60.2 years; 73.3% were non-Hispanic White, 4.9% were Black, 9.4% were Hispanic, and 1.6% were women whose ethnicity was unknown. Approximately 90% of the women were at stage I to stage II at initial diagnosis.

Overall, 340 (6.8%) had incident fractures during the follow-up period. The incident fractures included 46 hip, 104 vertebral, 78 humerus, and 137 wrist fractures. Significantly more women with hip fracture (43.5%) were age 80 years or older, compared with less than 25% of women with vertebral fractures (22.1%), humerus (19.2%), or wrist fracture (15.3%).

Pathologic fractures accounted for 22 of 104 incident vertebral fractures (21.2%) and fewer than 5 of 46 incident hip fractures (8.7%); few wrist and humerus fractures were pathologic. According to tumor stage, 15 of 87 (17.2%) vertebral fractures in women with initial stage I and II were pathologic, compared to 7 of 17 (41.2%) in women with initial stage III to stage IV breast cancer (P < .05).

The results emphasized the need to consider vertebral fracture risk in women with breast cancer, notably advanced stage cancer, as approximately one-third of the incident vertebral fractures in this subset of patients was deemed cancer-related, the researchers noted.

“As the axial skeleton is a common site for breast cancer metastasis and vertebrae a common site for pathologic fracture, primary care physicians should consider the possibility of pathologic fracture in women with higher risk based on advanced-stage cancer history,” the researchers wrote.

The study findings were limited by several factors, including the lack of data on fracture risk factors, treatment, and chemotherapy, and the inclusion only of clinically diagnosed fractures and not asymptomatic vertebral fractures, the researchers noted. However, the results were strengthened by the large sample size and comprehensive fracture assessment, they said. Additional studies to examine nonpathologic fracture risk according to breast cancer treatment, such as the use of aromatase inhibitors versus cytotoxic chemotherapy, may inform which women would benefit from more aggressive osteoporotic fracture prevention, they concluded.
 

Findings inform shared decision-making

“This study highlights the apparent association between an initial diagnosis of stage III or IV breast cancer and an increased risk for pathologic vertebral fracture,” said Constance Bohon, MD, a gynecologist in private practice in Washington, D.C., in an interview. “Most likely this finding is secondary to breast cancer metastases,” Dr. Bohon noted. However, she questioned whether there is a difference in fracture rates between women who received only aromatase inhibitors, those who received tamoxifen, and those who received both treatments.

“Additional data to determine the age of menopause, exercise frequency, current weight, and family history of osteoporosis may serve to identify those at highest risk for pathologic vertebral fracture,” said Dr. Bohon. “Until further data are available, clinicians should review this study and counsel their patients regarding options to potentially mitigate their apparent increased risk for pathologic vertebral fracture,” she emphasized.

The study was supported by the National Cancer Institute, National Institutes of Health, and the Research Program on Genes, Environment, and Health of Kaiser Permanente Northern California. The researchers had no financial conflicts to disclose. Dr. Bohon had no financial conflicts to disclose but serves on the Editorial Advisory Board of Ob.Gyn. News.

obnews@mdedge.com

Women with a history of stage III to stage IV breast cancer had significantly more pathologic vertebral fractures compared to those with stage I and stage II disease, based on data from approximately 5,000 adult women.

Breast cancer remains associated with increased fracture risk in part because of estrogen deficiency, aromatase inhibitors, frailty, and skeletal metastases, wrote Joan C. Lo, MD, of Kaiser Permanente Northern California, Oakland, and colleagues. Fractures associated with these factors have been studied, but many of the existing epidemiologic studies lack detail on fractures related to cancer, they noted. The researchers examined the association between pathologic fractures and major osteoporotic fractures in women with invasive breast cancer who received endocrine therapy.

In a study published in JAMA Network Open (2021 Nov 18. doi: 10.1001/jamanetworkopen.2021.33861), the researchers reviewed data from 5,010 women enrolled in the Pathways Study (3,312 women) or Research Program on Genes, Environment, and Health (RPGEH) study (1,698 women) with newly diagnosed invasive breast cancer who received endocrine therapy. The women were followed for up to 10 years for incident fracture, with a median follow-up period of 6.7 years.

The average age of the women was 60.2 years; 73.3% were non-Hispanic White, 4.9% were Black, 9.4% were Hispanic, and 1.6% were women whose ethnicity was unknown. Approximately 90% of the women were at stage I to stage II at initial diagnosis.

Overall, 340 (6.8%) had incident fractures during the follow-up period. The incident fractures included 46 hip, 104 vertebral, 78 humerus, and 137 wrist fractures. Significantly more women with hip fracture (43.5%) were age 80 years or older, compared with less than 25% of women with vertebral fractures (22.1%), humerus (19.2%), or wrist fracture (15.3%).

Pathologic fractures accounted for 22 of 104 incident vertebral fractures (21.2%) and fewer than 5 of 46 incident hip fractures (8.7%); few wrist and humerus fractures were pathologic. According to tumor stage, 15 of 87 (17.2%) vertebral fractures in women with initial stage I and II were pathologic, compared to 7 of 17 (41.2%) in women with initial stage III to stage IV breast cancer (P < .05).

The results emphasized the need to consider vertebral fracture risk in women with breast cancer, notably advanced stage cancer, as approximately one-third of the incident vertebral fractures in this subset of patients was deemed cancer-related, the researchers noted.

“As the axial skeleton is a common site for breast cancer metastasis and vertebrae a common site for pathologic fracture, primary care physicians should consider the possibility of pathologic fracture in women with higher risk based on advanced-stage cancer history,” the researchers wrote.

The study findings were limited by several factors, including the lack of data on fracture risk factors, treatment, and chemotherapy, and the inclusion only of clinically diagnosed fractures and not asymptomatic vertebral fractures, the researchers noted. However, the results were strengthened by the large sample size and comprehensive fracture assessment, they said. Additional studies to examine nonpathologic fracture risk according to breast cancer treatment, such as the use of aromatase inhibitors versus cytotoxic chemotherapy, may inform which women would benefit from more aggressive osteoporotic fracture prevention, they concluded.
 

Findings inform shared decision-making

“This study highlights the apparent association between an initial diagnosis of stage III or IV breast cancer and an increased risk for pathologic vertebral fracture,” said Constance Bohon, MD, a gynecologist in private practice in Washington, D.C., in an interview. “Most likely this finding is secondary to breast cancer metastases,” Dr. Bohon noted. However, she questioned whether there is a difference in fracture rates between women who received only aromatase inhibitors, those who received tamoxifen, and those who received both treatments.

“Additional data to determine the age of menopause, exercise frequency, current weight, and family history of osteoporosis may serve to identify those at highest risk for pathologic vertebral fracture,” said Dr. Bohon. “Until further data are available, clinicians should review this study and counsel their patients regarding options to potentially mitigate their apparent increased risk for pathologic vertebral fracture,” she emphasized.

The study was supported by the National Cancer Institute, National Institutes of Health, and the Research Program on Genes, Environment, and Health of Kaiser Permanente Northern California. The researchers had no financial conflicts to disclose. Dr. Bohon had no financial conflicts to disclose but serves on the Editorial Advisory Board of Ob.Gyn. News.

obnews@mdedge.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.

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.

Using sunscreen and following other sun-protective behaviors such as wearing long sleeves or staying in the shade do not decrease bone mineral density overall or increase the risk of osteoporotic fracture, according to a new study that included more than 3,000 men and women.

Aja Koska/Getty Images

“We have objective data for the first time, and in a large-scale representative population of the U.S. adults, to indicate sun protection is not associated with negative bone-related outcomes,” said study lead author Mohsen Afarideh, MD, MPH, a postdoctoral research fellow at the autoimmune skin diseases unit at the University of Pennsylvania, Philadelphia.

The study, published online in JAMA Dermatology, goes a step further than previous research by others that has found sunscreen use does not compromise vitamin D synthesis and has little effect on circulating 25-hydroxyvitamin D levels.

In the new study, researchers looked at three sun-protective behaviors – sunscreen use, staying in the shade, wearing long sleeves – and their effects on bone mineral density and the risk of fractures.

While the effects of sun-protective habits on blood levels of vitamin D and BMD scores are important, ‘’what we are more interested to know is if the sun-protective behaviors actually cause or increase the risk of fracture,” Dr. Afarideh said in an interview. “The answer to that is a firm ‘No.’ These data are very reassuring and will help clinicians to keep recommending sun protection to the public.”

Study details

Dr. Afarideh and his colleagues from the Mayo Clinic in Rochester, Minn., looked at data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2018, obtaining final information on 3,403 men and women, ages 20-59, who completed a dermatology questionnaire The men and women reported on the three sun-protective habits, and noted whether they followed these practices always or most of the time, sometimes, or never or rarely.

The frequency of the three behaviors was not widespread. Frequent staying in the shade was reported by 31.6% of the sample, wearing long sleeves by 11.8%, and sunscreen use by 26.1%.

The researchers also had data on the participants’ bone mineral density (BMD) scores along with dietary information such as milk consumption, vitamin D supplement use, taking steroid drugs, and exercise activity.

“Moderate sunscreen use was linked with a slightly lower lumbar BMD score,” Dr. Afarideh said, which was “the only significant association that could be interpreted as concerning.” And this was more likely to be seen in older respondents, he said.

However, otherwise they found the practice of the three behaviors was not associated with lower total or site-specific BMD z scores, nor was it linked with an increased risk of osteoporotic fractures. (The BMD z score compares an individual’s bone density to the average bone density of someone their same age and gender.)

The focus on fracture risk is the more important outcome, Dr. Afarideh said. And they found no increased risk overall of osteoporotic fractures in those who practiced sun-protective behaviors.

Moderate to frequent staying in the shade was actually linked with a reduced prevalence of spine fractures in the multivariate model (odds ratio, 0.19; 95% confidence interval, 0.04-0.86, P = .02). The researchers say that may be attributable to these respondents also being careful in other areas of life, such as avoiding falls and not participating in high-risk activities that would increase the chance of fractures. “However, this is just an assumption,” Dr. Afarideh said.

Expert perspectives

Other dermatologists not involved in the new research said the study results provide some “real-world” information that’s valuable for clinicians to share with patients.

“I think this is an important study on multiple levels,” said Henry W. Lim, MD, a former president of the American Academy of Dermatology who is a member of the department of dermatology and senior vice president of academic affairs at Henry Ford Health System, Detroit. “It is a well-done study, involving a large number. It is a real-life situation, asking people their photo protective behaviors and then looking at their bone mineral density.” The bottom line, he said: “Bone health is not affected by photo protection habits in real life.”

The findings are important but not surprising, said Antony R. Young, PhD, emeritus professor of experimental photobiology at St. John’s Institute of Dermatology, King’s College, London, who has researched sunscreens and vitamin D status. “My study showed that correct sunscreen use, albeit with a relatively low SPF of 15, did prevent sunburn in a high UVR [ultraviolet radiation] environment but did allow very good vitamin D synthesis. I think this is because the necessary dose of UVB is very low.”

Michele Green, MD, a New York dermatologist and clinical staff member at Lenox Hill Hospital there, said she often hears concerns about bone health from patients. “Every week, patients ask, ‘Why would I wear sunblock? Don’t I need sun for bone health? Don’t I need it for vitamin D?’’’

Now, she said, ‘’Dermatologists can point to the study and say ‘Don’t worry.’ It clarifies that using sunscreen won’t cause you to have osteoporosis.’’

Dr. Afarideh, who was a postdoctoral research fellow at the Mayo Clinic, and his coauthors, Megha M. Tollefson, MD, and Julio C. Sartori-Valinotti, of the Mayo Clinic, and Dr. Green had no disclosures. Dr. Lim and Dr. Young consult for the sunscreen industry.

Using sunscreen and following other sun-protective behaviors such as wearing long sleeves or staying in the shade do not decrease bone mineral density overall or increase the risk of osteoporotic fracture, according to a new study that included more than 3,000 men and women.

Aja Koska/Getty Images

“We have objective data for the first time, and in a large-scale representative population of the U.S. adults, to indicate sun protection is not associated with negative bone-related outcomes,” said study lead author Mohsen Afarideh, MD, MPH, a postdoctoral research fellow at the autoimmune skin diseases unit at the University of Pennsylvania, Philadelphia.

The study, published online in JAMA Dermatology, goes a step further than previous research by others that has found sunscreen use does not compromise vitamin D synthesis and has little effect on circulating 25-hydroxyvitamin D levels.

In the new study, researchers looked at three sun-protective behaviors – sunscreen use, staying in the shade, wearing long sleeves – and their effects on bone mineral density and the risk of fractures.

While the effects of sun-protective habits on blood levels of vitamin D and BMD scores are important, ‘’what we are more interested to know is if the sun-protective behaviors actually cause or increase the risk of fracture,” Dr. Afarideh said in an interview. “The answer to that is a firm ‘No.’ These data are very reassuring and will help clinicians to keep recommending sun protection to the public.”

Study details

Dr. Afarideh and his colleagues from the Mayo Clinic in Rochester, Minn., looked at data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2018, obtaining final information on 3,403 men and women, ages 20-59, who completed a dermatology questionnaire The men and women reported on the three sun-protective habits, and noted whether they followed these practices always or most of the time, sometimes, or never or rarely.

The frequency of the three behaviors was not widespread. Frequent staying in the shade was reported by 31.6% of the sample, wearing long sleeves by 11.8%, and sunscreen use by 26.1%.

The researchers also had data on the participants’ bone mineral density (BMD) scores along with dietary information such as milk consumption, vitamin D supplement use, taking steroid drugs, and exercise activity.

“Moderate sunscreen use was linked with a slightly lower lumbar BMD score,” Dr. Afarideh said, which was “the only significant association that could be interpreted as concerning.” And this was more likely to be seen in older respondents, he said.

However, otherwise they found the practice of the three behaviors was not associated with lower total or site-specific BMD z scores, nor was it linked with an increased risk of osteoporotic fractures. (The BMD z score compares an individual’s bone density to the average bone density of someone their same age and gender.)

The focus on fracture risk is the more important outcome, Dr. Afarideh said. And they found no increased risk overall of osteoporotic fractures in those who practiced sun-protective behaviors.

Moderate to frequent staying in the shade was actually linked with a reduced prevalence of spine fractures in the multivariate model (odds ratio, 0.19; 95% confidence interval, 0.04-0.86, P = .02). The researchers say that may be attributable to these respondents also being careful in other areas of life, such as avoiding falls and not participating in high-risk activities that would increase the chance of fractures. “However, this is just an assumption,” Dr. Afarideh said.

Expert perspectives

Other dermatologists not involved in the new research said the study results provide some “real-world” information that’s valuable for clinicians to share with patients.

“I think this is an important study on multiple levels,” said Henry W. Lim, MD, a former president of the American Academy of Dermatology who is a member of the department of dermatology and senior vice president of academic affairs at Henry Ford Health System, Detroit. “It is a well-done study, involving a large number. It is a real-life situation, asking people their photo protective behaviors and then looking at their bone mineral density.” The bottom line, he said: “Bone health is not affected by photo protection habits in real life.”

The findings are important but not surprising, said Antony R. Young, PhD, emeritus professor of experimental photobiology at St. John’s Institute of Dermatology, King’s College, London, who has researched sunscreens and vitamin D status. “My study showed that correct sunscreen use, albeit with a relatively low SPF of 15, did prevent sunburn in a high UVR [ultraviolet radiation] environment but did allow very good vitamin D synthesis. I think this is because the necessary dose of UVB is very low.”

Michele Green, MD, a New York dermatologist and clinical staff member at Lenox Hill Hospital there, said she often hears concerns about bone health from patients. “Every week, patients ask, ‘Why would I wear sunblock? Don’t I need sun for bone health? Don’t I need it for vitamin D?’’’

Now, she said, ‘’Dermatologists can point to the study and say ‘Don’t worry.’ It clarifies that using sunscreen won’t cause you to have osteoporosis.’’

Dr. Afarideh, who was a postdoctoral research fellow at the Mayo Clinic, and his coauthors, Megha M. Tollefson, MD, and Julio C. Sartori-Valinotti, of the Mayo Clinic, and Dr. Green had no disclosures. Dr. Lim and Dr. Young consult for the sunscreen industry.

Using sunscreen and following other sun-protective behaviors such as wearing long sleeves or staying in the shade do not decrease bone mineral density overall or increase the risk of osteoporotic fracture, according to a new study that included more than 3,000 men and women.

Aja Koska/Getty Images

“We have objective data for the first time, and in a large-scale representative population of the U.S. adults, to indicate sun protection is not associated with negative bone-related outcomes,” said study lead author Mohsen Afarideh, MD, MPH, a postdoctoral research fellow at the autoimmune skin diseases unit at the University of Pennsylvania, Philadelphia.

The study, published online in JAMA Dermatology, goes a step further than previous research by others that has found sunscreen use does not compromise vitamin D synthesis and has little effect on circulating 25-hydroxyvitamin D levels.

In the new study, researchers looked at three sun-protective behaviors – sunscreen use, staying in the shade, wearing long sleeves – and their effects on bone mineral density and the risk of fractures.

While the effects of sun-protective habits on blood levels of vitamin D and BMD scores are important, ‘’what we are more interested to know is if the sun-protective behaviors actually cause or increase the risk of fracture,” Dr. Afarideh said in an interview. “The answer to that is a firm ‘No.’ These data are very reassuring and will help clinicians to keep recommending sun protection to the public.”

Study details

Dr. Afarideh and his colleagues from the Mayo Clinic in Rochester, Minn., looked at data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2018, obtaining final information on 3,403 men and women, ages 20-59, who completed a dermatology questionnaire The men and women reported on the three sun-protective habits, and noted whether they followed these practices always or most of the time, sometimes, or never or rarely.

The frequency of the three behaviors was not widespread. Frequent staying in the shade was reported by 31.6% of the sample, wearing long sleeves by 11.8%, and sunscreen use by 26.1%.

The researchers also had data on the participants’ bone mineral density (BMD) scores along with dietary information such as milk consumption, vitamin D supplement use, taking steroid drugs, and exercise activity.

“Moderate sunscreen use was linked with a slightly lower lumbar BMD score,” Dr. Afarideh said, which was “the only significant association that could be interpreted as concerning.” And this was more likely to be seen in older respondents, he said.

However, otherwise they found the practice of the three behaviors was not associated with lower total or site-specific BMD z scores, nor was it linked with an increased risk of osteoporotic fractures. (The BMD z score compares an individual’s bone density to the average bone density of someone their same age and gender.)

The focus on fracture risk is the more important outcome, Dr. Afarideh said. And they found no increased risk overall of osteoporotic fractures in those who practiced sun-protective behaviors.

Moderate to frequent staying in the shade was actually linked with a reduced prevalence of spine fractures in the multivariate model (odds ratio, 0.19; 95% confidence interval, 0.04-0.86, P = .02). The researchers say that may be attributable to these respondents also being careful in other areas of life, such as avoiding falls and not participating in high-risk activities that would increase the chance of fractures. “However, this is just an assumption,” Dr. Afarideh said.

Expert perspectives

Other dermatologists not involved in the new research said the study results provide some “real-world” information that’s valuable for clinicians to share with patients.

“I think this is an important study on multiple levels,” said Henry W. Lim, MD, a former president of the American Academy of Dermatology who is a member of the department of dermatology and senior vice president of academic affairs at Henry Ford Health System, Detroit. “It is a well-done study, involving a large number. It is a real-life situation, asking people their photo protective behaviors and then looking at their bone mineral density.” The bottom line, he said: “Bone health is not affected by photo protection habits in real life.”

The findings are important but not surprising, said Antony R. Young, PhD, emeritus professor of experimental photobiology at St. John’s Institute of Dermatology, King’s College, London, who has researched sunscreens and vitamin D status. “My study showed that correct sunscreen use, albeit with a relatively low SPF of 15, did prevent sunburn in a high UVR [ultraviolet radiation] environment but did allow very good vitamin D synthesis. I think this is because the necessary dose of UVB is very low.”

Michele Green, MD, a New York dermatologist and clinical staff member at Lenox Hill Hospital there, said she often hears concerns about bone health from patients. “Every week, patients ask, ‘Why would I wear sunblock? Don’t I need sun for bone health? Don’t I need it for vitamin D?’’’

Now, she said, ‘’Dermatologists can point to the study and say ‘Don’t worry.’ It clarifies that using sunscreen won’t cause you to have osteoporosis.’’

Dr. Afarideh, who was a postdoctoral research fellow at the Mayo Clinic, and his coauthors, Megha M. Tollefson, MD, and Julio C. Sartori-Valinotti, of the Mayo Clinic, and Dr. Green had no disclosures. Dr. Lim and Dr. Young consult for the sunscreen industry.

Use of sodium-glucose cotransporter-2 (SGLT2) inhibitors does not appear to raise the risk for fractures in older adults, new research suggests.

The data come from a nationwide propensity score-matched study of U.S. Medicare recipients with type 2 diabetes who were new users of either an SGLT2 inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or a glucagon-like peptide (GLP-1) receptor agonist.

“The use of SGLT2 inhibitors was not associated with an increased risk of nontraumatic fractures compared with DPP-4 inhibitors or GLP-1 agonists. Results were consistent across categories of sex, frailty, age, and insulin use,” say Min Zhuo, MD, of Harvard Medical School, Boston, and colleagues, who published their work online October 27 in JAMA Network Open.

“Our results add to the evidence base evaluating the safety profile of SGLT2 inhibitors in older adults outside of [randomized controlled trials] and further characterize the risk-benefit balance of SGLT2 inhibitors in clinical practice,” they write.

Asked to comment, Simeon I. Taylor, MD, PhD, told this news organization, “This is a high-quality study that is generally reassuring that relatively short, less than 1 year, treatment with an SGLT2 inhibitor does not appear to significantly increase the risk of bone fractures.”

However, Dr. Taylor, of the Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, also noted: “Notwithstanding these reassuring data, the paper also does a good job of pointing out important limitations.”

“Most importantly, these data do not address questions related to the risk of long-term chronic therapy. It is instructive to refer back to the published data demonstrating an approximately 2-year lag before a significant increase in the risk of fracture was observed in rosiglitazone-treated patients in the ADOPT study. The length of the lag is likely related to the baseline bone mineral density at the time drug therapy is initiated. These considerations may contribute to the observed variation in bone-related outcomes in different studies.”

Concern about SGLT2 inhibitors and fractures first arose in 2017 from the CANVAS study, in which the overall fracture risk with canagliflozin was a significant 26% higher than placebo. However, subsequent larger randomized trials of canagliflozin and other SGLT2 inhibitors did not find the same risk.

In addition, previous observational studies in younger adults have also not found use of SGLT2 inhibitors to be associated with increased fracture risk compared with DPP-4 inhibitors or GLP-1 agonists.
 

Understanding fracture risk with SGLT2 inhibitors is ‘critical’

Older adults with type 2 diabetes may benefit from reductions in atherosclerotic cardiovascular events, hospitalization for heart failure, end-stage kidney disease, and death associated with SGLT2 inhibitors, but the fact that aging may have negative effects on bone metabolism means “understanding the fracture risk associated with SGLT2 inhibitors in older adults with type 2 diabetes is critical,” say Dr. Zhuo and colleagues.

In the current study, they analyzed claims data for Medicare beneficiaries aged 66 years and older (1 year past Medicare eligibility) who were newly prescribed an SGLT2 inhibitor, DPP-4 inhibitor, or GLP-1 agonist between April 1, 2013 and Dec. 31, 2017.

A total of 45,889 patients from each treatment group were propensity-matched using 58 baseline characteristics, for a total of 137,667 patients.

After matching, there were 501 events of the primary composite outcome (nontraumatic pelvic fracture, hip fracture requiring surgery, or humerus, radius, or ulna fracture requiring intervention) within 30 days. By treatment group, fracture rates per 1,000 person-years were 4.69, 5.26, and 4.71 for SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 agonists respectively.

The differences between patients taking DPP-4 inhibitors or GLP-1 agonists compared with SGLT2 inhibitors were not significant, with hazard ratios of 0.90 and 1.00, respectively.     

Results remained consistent in various sensitivity and subgroup analyses, including limiting the data to just the canagliflozin group. Overall, the fracture rate was greater with female sex, frailty, older age, and insulin use, consistent across drug classes.

The risks for falls and hypoglycemia were lower in the SGLT2 inhibitor versus matched DPP-4 inhibitor groups (hazard ratio, 0.82), and there was no difference in syncope. None of those differences were significant for the SGLT2 inhibitor group compared with the GLP-1 agonist group.

Consistent with previous data, the risk for diabetic ketoacidosis was higher with SGLT2 inhibitors versus DPP-4 inhibitors and GLP-1 agonists (HR, 1.29 and 1.58), and the risk for heart failure hospitalization was lower (HR, 0.42 and 0.69).

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, Harvard Medical School. Dr. Zhuo was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Taylor is a consultant for Ionis Pharmaceuticals.

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

Use of sodium-glucose cotransporter-2 (SGLT2) inhibitors does not appear to raise the risk for fractures in older adults, new research suggests.

The data come from a nationwide propensity score-matched study of U.S. Medicare recipients with type 2 diabetes who were new users of either an SGLT2 inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or a glucagon-like peptide (GLP-1) receptor agonist.

“The use of SGLT2 inhibitors was not associated with an increased risk of nontraumatic fractures compared with DPP-4 inhibitors or GLP-1 agonists. Results were consistent across categories of sex, frailty, age, and insulin use,” say Min Zhuo, MD, of Harvard Medical School, Boston, and colleagues, who published their work online October 27 in JAMA Network Open.

“Our results add to the evidence base evaluating the safety profile of SGLT2 inhibitors in older adults outside of [randomized controlled trials] and further characterize the risk-benefit balance of SGLT2 inhibitors in clinical practice,” they write.

Asked to comment, Simeon I. Taylor, MD, PhD, told this news organization, “This is a high-quality study that is generally reassuring that relatively short, less than 1 year, treatment with an SGLT2 inhibitor does not appear to significantly increase the risk of bone fractures.”

However, Dr. Taylor, of the Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, also noted: “Notwithstanding these reassuring data, the paper also does a good job of pointing out important limitations.”

“Most importantly, these data do not address questions related to the risk of long-term chronic therapy. It is instructive to refer back to the published data demonstrating an approximately 2-year lag before a significant increase in the risk of fracture was observed in rosiglitazone-treated patients in the ADOPT study. The length of the lag is likely related to the baseline bone mineral density at the time drug therapy is initiated. These considerations may contribute to the observed variation in bone-related outcomes in different studies.”

Concern about SGLT2 inhibitors and fractures first arose in 2017 from the CANVAS study, in which the overall fracture risk with canagliflozin was a significant 26% higher than placebo. However, subsequent larger randomized trials of canagliflozin and other SGLT2 inhibitors did not find the same risk.

In addition, previous observational studies in younger adults have also not found use of SGLT2 inhibitors to be associated with increased fracture risk compared with DPP-4 inhibitors or GLP-1 agonists.
 

Understanding fracture risk with SGLT2 inhibitors is ‘critical’

Older adults with type 2 diabetes may benefit from reductions in atherosclerotic cardiovascular events, hospitalization for heart failure, end-stage kidney disease, and death associated with SGLT2 inhibitors, but the fact that aging may have negative effects on bone metabolism means “understanding the fracture risk associated with SGLT2 inhibitors in older adults with type 2 diabetes is critical,” say Dr. Zhuo and colleagues.

In the current study, they analyzed claims data for Medicare beneficiaries aged 66 years and older (1 year past Medicare eligibility) who were newly prescribed an SGLT2 inhibitor, DPP-4 inhibitor, or GLP-1 agonist between April 1, 2013 and Dec. 31, 2017.

A total of 45,889 patients from each treatment group were propensity-matched using 58 baseline characteristics, for a total of 137,667 patients.

After matching, there were 501 events of the primary composite outcome (nontraumatic pelvic fracture, hip fracture requiring surgery, or humerus, radius, or ulna fracture requiring intervention) within 30 days. By treatment group, fracture rates per 1,000 person-years were 4.69, 5.26, and 4.71 for SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 agonists respectively.

The differences between patients taking DPP-4 inhibitors or GLP-1 agonists compared with SGLT2 inhibitors were not significant, with hazard ratios of 0.90 and 1.00, respectively.     

Results remained consistent in various sensitivity and subgroup analyses, including limiting the data to just the canagliflozin group. Overall, the fracture rate was greater with female sex, frailty, older age, and insulin use, consistent across drug classes.

The risks for falls and hypoglycemia were lower in the SGLT2 inhibitor versus matched DPP-4 inhibitor groups (hazard ratio, 0.82), and there was no difference in syncope. None of those differences were significant for the SGLT2 inhibitor group compared with the GLP-1 agonist group.

Consistent with previous data, the risk for diabetic ketoacidosis was higher with SGLT2 inhibitors versus DPP-4 inhibitors and GLP-1 agonists (HR, 1.29 and 1.58), and the risk for heart failure hospitalization was lower (HR, 0.42 and 0.69).

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, Harvard Medical School. Dr. Zhuo was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Taylor is a consultant for Ionis Pharmaceuticals.

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

Use of sodium-glucose cotransporter-2 (SGLT2) inhibitors does not appear to raise the risk for fractures in older adults, new research suggests.

The data come from a nationwide propensity score-matched study of U.S. Medicare recipients with type 2 diabetes who were new users of either an SGLT2 inhibitor, a dipeptidyl peptidase 4 (DPP-4) inhibitor, or a glucagon-like peptide (GLP-1) receptor agonist.

“The use of SGLT2 inhibitors was not associated with an increased risk of nontraumatic fractures compared with DPP-4 inhibitors or GLP-1 agonists. Results were consistent across categories of sex, frailty, age, and insulin use,” say Min Zhuo, MD, of Harvard Medical School, Boston, and colleagues, who published their work online October 27 in JAMA Network Open.

“Our results add to the evidence base evaluating the safety profile of SGLT2 inhibitors in older adults outside of [randomized controlled trials] and further characterize the risk-benefit balance of SGLT2 inhibitors in clinical practice,” they write.

Asked to comment, Simeon I. Taylor, MD, PhD, told this news organization, “This is a high-quality study that is generally reassuring that relatively short, less than 1 year, treatment with an SGLT2 inhibitor does not appear to significantly increase the risk of bone fractures.”

However, Dr. Taylor, of the Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, also noted: “Notwithstanding these reassuring data, the paper also does a good job of pointing out important limitations.”

“Most importantly, these data do not address questions related to the risk of long-term chronic therapy. It is instructive to refer back to the published data demonstrating an approximately 2-year lag before a significant increase in the risk of fracture was observed in rosiglitazone-treated patients in the ADOPT study. The length of the lag is likely related to the baseline bone mineral density at the time drug therapy is initiated. These considerations may contribute to the observed variation in bone-related outcomes in different studies.”

Concern about SGLT2 inhibitors and fractures first arose in 2017 from the CANVAS study, in which the overall fracture risk with canagliflozin was a significant 26% higher than placebo. However, subsequent larger randomized trials of canagliflozin and other SGLT2 inhibitors did not find the same risk.

In addition, previous observational studies in younger adults have also not found use of SGLT2 inhibitors to be associated with increased fracture risk compared with DPP-4 inhibitors or GLP-1 agonists.
 

Understanding fracture risk with SGLT2 inhibitors is ‘critical’

Older adults with type 2 diabetes may benefit from reductions in atherosclerotic cardiovascular events, hospitalization for heart failure, end-stage kidney disease, and death associated with SGLT2 inhibitors, but the fact that aging may have negative effects on bone metabolism means “understanding the fracture risk associated with SGLT2 inhibitors in older adults with type 2 diabetes is critical,” say Dr. Zhuo and colleagues.

In the current study, they analyzed claims data for Medicare beneficiaries aged 66 years and older (1 year past Medicare eligibility) who were newly prescribed an SGLT2 inhibitor, DPP-4 inhibitor, or GLP-1 agonist between April 1, 2013 and Dec. 31, 2017.

A total of 45,889 patients from each treatment group were propensity-matched using 58 baseline characteristics, for a total of 137,667 patients.

After matching, there were 501 events of the primary composite outcome (nontraumatic pelvic fracture, hip fracture requiring surgery, or humerus, radius, or ulna fracture requiring intervention) within 30 days. By treatment group, fracture rates per 1,000 person-years were 4.69, 5.26, and 4.71 for SGLT2 inhibitors, DPP-4 inhibitors, and GLP-1 agonists respectively.

The differences between patients taking DPP-4 inhibitors or GLP-1 agonists compared with SGLT2 inhibitors were not significant, with hazard ratios of 0.90 and 1.00, respectively.     

Results remained consistent in various sensitivity and subgroup analyses, including limiting the data to just the canagliflozin group. Overall, the fracture rate was greater with female sex, frailty, older age, and insulin use, consistent across drug classes.

The risks for falls and hypoglycemia were lower in the SGLT2 inhibitor versus matched DPP-4 inhibitor groups (hazard ratio, 0.82), and there was no difference in syncope. None of those differences were significant for the SGLT2 inhibitor group compared with the GLP-1 agonist group.

Consistent with previous data, the risk for diabetic ketoacidosis was higher with SGLT2 inhibitors versus DPP-4 inhibitors and GLP-1 agonists (HR, 1.29 and 1.58), and the risk for heart failure hospitalization was lower (HR, 0.42 and 0.69).

The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, department of medicine, Brigham and Women’s Hospital, Harvard Medical School. Dr. Zhuo was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Taylor is a consultant for Ionis Pharmaceuticals.

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