Osteoporosis

“More is not necessarily better” when it comes to vitamin D supplements for women with adequate serum levels, new research suggests.

In a study of healthy 55- to 70-year-old women who took very-high-dose vitamin D supplements – either 4,000 IU/day or the previously identified “upper safe limit” of 10,000 IU/day – for 3 years had a significantly greater loss of total bone mineral density (BMD) at the radius and tibia than did women who took 400 IU/day. However, this effect was not seen in men. And the higher-dose vitamin D supplements did not improve bone strength in men or women.

But this was an exploratory post hoc analysis, and these were healthy community-dwelling adults with sufficient serum vitamin D levels (and no osteoporosis) at study entry, stressed lead researcher Lauren A. Burt, PhD, from the University of Calgary, in Alberta, Canada.

Dr. Burt presented these findings Sept. 11 at the virtual American Society of Bone and Mineral Research (ASBMR) 2020 annual meeting, and the study was also recently published online in the Journal of Bone and Mineral Research.

The results suggest that, “if you have normal bone density and adequate levels of vitamin D, there is no bone benefit in taking doses of vitamin D above the standard recommendations designed to prevent vitamin D deficiency, and doses at or above 4,000 IU/day might even be detrimental to bone, especially in females,” Dr. Burt said in an interview.

“These results are clinically relevant,” Dr. Burt and her coauthors wrote, “as vitamin D supplementation is widely administered to postmenopausal females for osteoporosis prevention.”

“Our findings do not support a benefit of high-dose vitamin D supplementation for bone health and raise the possibility of harm for females.”

Invited to comment, Meryl S. LeBoff, MD, of Harvard Medical School, Boston, said in an interview that this finding “warrants further research” because it is “important” to discover sex differences in bone responses to vitamin D.
 

“This doesn’t apply to osteoporosis”

Dr. LeBoff was lead author of a subanalysis of the Vitamin D and Omega-3 Trial (VITAL).

As she reported at last year’s ASBMR meeting, that analysis showed that, in healthy adults who did not have vitamin D insufficiency, taking vitamin D3 supplements for 2 years did not improve BMD, compared with placebo (recently published), nor was this linked with fewer fractures. 

Dr. LeBoff pointed out that the current study investigated “very high doses of vitamin D” – at least double the 2,000 IU/day doses examined in VITAL.

Also, the serum vitamin D levels in this study were “above what we considered the upper normal limit for our assay in our hospital,” she noted, and there was no placebo control.

“We did not see any adverse effects of 2,000 IU/day vitamin D,” Dr. LeBoff stressed.

“At the same time, we didn’t see any significant benefits in terms of bone density because they already had achieved a normal level of vitamin D sufficient for bone.”

But “this doesn’t apply to patients with vitamin D deficiency, patients with osteoporosis, or low bone mass, in which case we would recommend vitamin D.”

Some patients take more vitamin D than they need because they think more is better, said LeBoff, but this study suggests “more is not necessarily better.”

“There’s been a concern for several years that too much vitamin D may be associated with increased fractures,” she emphasized.
 

Post hoc analysis

The current study analyzed new data from the Calgary Vitamin D study.

That study found no benefit in BMD or bone strength (JAMA. 2019;322[8]:736-45), contrary to the researchers’ hypothesis that high-dose vitamin D supplements would be associated with greater calcium absorption and parathyroid hormone suppression and, thus, reduced age-related bone loss (improved bone density and strength).

Instead, they found a negative dose-response relationship, which “should be regarded as hypothesis generating, requiring confirmation with further research,” they wrote.

The current study sought to determine if there were sex differences in the effect of vitamin D supplements on bone health in this population.  

From October 2013 to December 2017, the Canada Vitamin D study enrolled 311 participants (53% male). To be eligible for the study, participants had to have serum 25-hydroxyvitamin D levels greater than 30 nmol/L and less than 125 nmol/L. They also needed to have adequate calcium intake (1,200 mg/day, as defined by the U.S. Institute of Medicine), or if not, they were instructed to take an appropriate calcium supplement dose.

Patients were randomized to receive 400, 4,000, or 10,000 IU/day of vitamin D3 cholecalciferol, given as 5 drops/day of liquid (Ddrops), with roughly 50 men and 50 women in each dose group.

Researchers selected the 400 IU/day dose as the comparator because the Institute of Medicine recommends a vitamin D intake of 600 IU/day for adults under age 70 years to provide the vitamin D needed for bone health. The typical Canadian diet includes 200-300 IU/day of vitamin D, so individuals would need a supplement of 400 IU/day to reach the recommended intake. The 4,000 IU/day dose is the recommended tolerable upper intake level, according to the Institute of Medicine. And the 10,000 IU/day dose is the tolerable upper intake level of vitamin D as identified in a review by Hathcock and colleagues (Am J Clin Nutr. 2007;85:6-18).

Participants underwent scans with high-resolution peripheral quantitative computed tomography (HR-pQCT) to measure total volumetric BMD at the radius and tibia at baseline, 6, 12, 24, and 36 months. Finite element analysis was used to estimate bone strength.

After 3 years, women had lost significantly more BMD at the radius after taking high-dose versus 400 IU/day of vitamin D. Losses in BMD at the tibia followed a similar trend but were smaller (Figure 1). There were no significant changes in this measure among men (Figure 2). 

There were also no significant changes in bone strength among men or women.

Biological mechanism remains to be determined

Dr. LeBoff said a “possible biological explanation” for the findings is that “women, particularly when they are younger, lose more bone than men.”

“Postmenopausal females do lose bone at an accelerated rate compared with males,” Dr. Burt agreed, “but at the time the study was designed, there was no reason to believe that high-dose vitamin D supplementation would accelerate the problem.”

“The biological mechanism of the vitamin D–related bone loss needs further investigation,” Dr. Burt added, “but there are laboratory data suggesting that supraphysiologic doses of active metabolites of vitamin D may stimulate bone resorption.”

The study was funded by the Pure North S’Energy Foundation. Dr. Burt has reported no relevant financial relationships. Disclosures for the other authors are listed with the article. Dr. LeBoff has reported receiving grants from the National Institutes of Health for the VITAL analysis.
 

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

“More is not necessarily better” when it comes to vitamin D supplements for women with adequate serum levels, new research suggests.

In a study of healthy 55- to 70-year-old women who took very-high-dose vitamin D supplements – either 4,000 IU/day or the previously identified “upper safe limit” of 10,000 IU/day – for 3 years had a significantly greater loss of total bone mineral density (BMD) at the radius and tibia than did women who took 400 IU/day. However, this effect was not seen in men. And the higher-dose vitamin D supplements did not improve bone strength in men or women.

But this was an exploratory post hoc analysis, and these were healthy community-dwelling adults with sufficient serum vitamin D levels (and no osteoporosis) at study entry, stressed lead researcher Lauren A. Burt, PhD, from the University of Calgary, in Alberta, Canada.

Dr. Burt presented these findings Sept. 11 at the virtual American Society of Bone and Mineral Research (ASBMR) 2020 annual meeting, and the study was also recently published online in the Journal of Bone and Mineral Research.

The results suggest that, “if you have normal bone density and adequate levels of vitamin D, there is no bone benefit in taking doses of vitamin D above the standard recommendations designed to prevent vitamin D deficiency, and doses at or above 4,000 IU/day might even be detrimental to bone, especially in females,” Dr. Burt said in an interview.

“These results are clinically relevant,” Dr. Burt and her coauthors wrote, “as vitamin D supplementation is widely administered to postmenopausal females for osteoporosis prevention.”

“Our findings do not support a benefit of high-dose vitamin D supplementation for bone health and raise the possibility of harm for females.”

Invited to comment, Meryl S. LeBoff, MD, of Harvard Medical School, Boston, said in an interview that this finding “warrants further research” because it is “important” to discover sex differences in bone responses to vitamin D.
 

“This doesn’t apply to osteoporosis”

Dr. LeBoff was lead author of a subanalysis of the Vitamin D and Omega-3 Trial (VITAL).

As she reported at last year’s ASBMR meeting, that analysis showed that, in healthy adults who did not have vitamin D insufficiency, taking vitamin D3 supplements for 2 years did not improve BMD, compared with placebo (recently published), nor was this linked with fewer fractures. 

Dr. LeBoff pointed out that the current study investigated “very high doses of vitamin D” – at least double the 2,000 IU/day doses examined in VITAL.

Also, the serum vitamin D levels in this study were “above what we considered the upper normal limit for our assay in our hospital,” she noted, and there was no placebo control.

“We did not see any adverse effects of 2,000 IU/day vitamin D,” Dr. LeBoff stressed.

“At the same time, we didn’t see any significant benefits in terms of bone density because they already had achieved a normal level of vitamin D sufficient for bone.”

But “this doesn’t apply to patients with vitamin D deficiency, patients with osteoporosis, or low bone mass, in which case we would recommend vitamin D.”

Some patients take more vitamin D than they need because they think more is better, said LeBoff, but this study suggests “more is not necessarily better.”

“There’s been a concern for several years that too much vitamin D may be associated with increased fractures,” she emphasized.
 

Post hoc analysis

The current study analyzed new data from the Calgary Vitamin D study.

That study found no benefit in BMD or bone strength (JAMA. 2019;322[8]:736-45), contrary to the researchers’ hypothesis that high-dose vitamin D supplements would be associated with greater calcium absorption and parathyroid hormone suppression and, thus, reduced age-related bone loss (improved bone density and strength).

Instead, they found a negative dose-response relationship, which “should be regarded as hypothesis generating, requiring confirmation with further research,” they wrote.

The current study sought to determine if there were sex differences in the effect of vitamin D supplements on bone health in this population.  

From October 2013 to December 2017, the Canada Vitamin D study enrolled 311 participants (53% male). To be eligible for the study, participants had to have serum 25-hydroxyvitamin D levels greater than 30 nmol/L and less than 125 nmol/L. They also needed to have adequate calcium intake (1,200 mg/day, as defined by the U.S. Institute of Medicine), or if not, they were instructed to take an appropriate calcium supplement dose.

Patients were randomized to receive 400, 4,000, or 10,000 IU/day of vitamin D3 cholecalciferol, given as 5 drops/day of liquid (Ddrops), with roughly 50 men and 50 women in each dose group.

Researchers selected the 400 IU/day dose as the comparator because the Institute of Medicine recommends a vitamin D intake of 600 IU/day for adults under age 70 years to provide the vitamin D needed for bone health. The typical Canadian diet includes 200-300 IU/day of vitamin D, so individuals would need a supplement of 400 IU/day to reach the recommended intake. The 4,000 IU/day dose is the recommended tolerable upper intake level, according to the Institute of Medicine. And the 10,000 IU/day dose is the tolerable upper intake level of vitamin D as identified in a review by Hathcock and colleagues (Am J Clin Nutr. 2007;85:6-18).

Participants underwent scans with high-resolution peripheral quantitative computed tomography (HR-pQCT) to measure total volumetric BMD at the radius and tibia at baseline, 6, 12, 24, and 36 months. Finite element analysis was used to estimate bone strength.

After 3 years, women had lost significantly more BMD at the radius after taking high-dose versus 400 IU/day of vitamin D. Losses in BMD at the tibia followed a similar trend but were smaller (Figure 1). There were no significant changes in this measure among men (Figure 2). 

There were also no significant changes in bone strength among men or women.

Biological mechanism remains to be determined

Dr. LeBoff said a “possible biological explanation” for the findings is that “women, particularly when they are younger, lose more bone than men.”

“Postmenopausal females do lose bone at an accelerated rate compared with males,” Dr. Burt agreed, “but at the time the study was designed, there was no reason to believe that high-dose vitamin D supplementation would accelerate the problem.”

“The biological mechanism of the vitamin D–related bone loss needs further investigation,” Dr. Burt added, “but there are laboratory data suggesting that supraphysiologic doses of active metabolites of vitamin D may stimulate bone resorption.”

The study was funded by the Pure North S’Energy Foundation. Dr. Burt has reported no relevant financial relationships. Disclosures for the other authors are listed with the article. Dr. LeBoff has reported receiving grants from the National Institutes of Health for the VITAL analysis.
 

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

“More is not necessarily better” when it comes to vitamin D supplements for women with adequate serum levels, new research suggests.

In a study of healthy 55- to 70-year-old women who took very-high-dose vitamin D supplements – either 4,000 IU/day or the previously identified “upper safe limit” of 10,000 IU/day – for 3 years had a significantly greater loss of total bone mineral density (BMD) at the radius and tibia than did women who took 400 IU/day. However, this effect was not seen in men. And the higher-dose vitamin D supplements did not improve bone strength in men or women.

But this was an exploratory post hoc analysis, and these were healthy community-dwelling adults with sufficient serum vitamin D levels (and no osteoporosis) at study entry, stressed lead researcher Lauren A. Burt, PhD, from the University of Calgary, in Alberta, Canada.

Dr. Burt presented these findings Sept. 11 at the virtual American Society of Bone and Mineral Research (ASBMR) 2020 annual meeting, and the study was also recently published online in the Journal of Bone and Mineral Research.

The results suggest that, “if you have normal bone density and adequate levels of vitamin D, there is no bone benefit in taking doses of vitamin D above the standard recommendations designed to prevent vitamin D deficiency, and doses at or above 4,000 IU/day might even be detrimental to bone, especially in females,” Dr. Burt said in an interview.

“These results are clinically relevant,” Dr. Burt and her coauthors wrote, “as vitamin D supplementation is widely administered to postmenopausal females for osteoporosis prevention.”

“Our findings do not support a benefit of high-dose vitamin D supplementation for bone health and raise the possibility of harm for females.”

Invited to comment, Meryl S. LeBoff, MD, of Harvard Medical School, Boston, said in an interview that this finding “warrants further research” because it is “important” to discover sex differences in bone responses to vitamin D.
 

“This doesn’t apply to osteoporosis”

Dr. LeBoff was lead author of a subanalysis of the Vitamin D and Omega-3 Trial (VITAL).

As she reported at last year’s ASBMR meeting, that analysis showed that, in healthy adults who did not have vitamin D insufficiency, taking vitamin D3 supplements for 2 years did not improve BMD, compared with placebo (recently published), nor was this linked with fewer fractures. 

Dr. LeBoff pointed out that the current study investigated “very high doses of vitamin D” – at least double the 2,000 IU/day doses examined in VITAL.

Also, the serum vitamin D levels in this study were “above what we considered the upper normal limit for our assay in our hospital,” she noted, and there was no placebo control.

“We did not see any adverse effects of 2,000 IU/day vitamin D,” Dr. LeBoff stressed.

“At the same time, we didn’t see any significant benefits in terms of bone density because they already had achieved a normal level of vitamin D sufficient for bone.”

But “this doesn’t apply to patients with vitamin D deficiency, patients with osteoporosis, or low bone mass, in which case we would recommend vitamin D.”

Some patients take more vitamin D than they need because they think more is better, said LeBoff, but this study suggests “more is not necessarily better.”

“There’s been a concern for several years that too much vitamin D may be associated with increased fractures,” she emphasized.
 

Post hoc analysis

The current study analyzed new data from the Calgary Vitamin D study.

That study found no benefit in BMD or bone strength (JAMA. 2019;322[8]:736-45), contrary to the researchers’ hypothesis that high-dose vitamin D supplements would be associated with greater calcium absorption and parathyroid hormone suppression and, thus, reduced age-related bone loss (improved bone density and strength).

Instead, they found a negative dose-response relationship, which “should be regarded as hypothesis generating, requiring confirmation with further research,” they wrote.

The current study sought to determine if there were sex differences in the effect of vitamin D supplements on bone health in this population.  

From October 2013 to December 2017, the Canada Vitamin D study enrolled 311 participants (53% male). To be eligible for the study, participants had to have serum 25-hydroxyvitamin D levels greater than 30 nmol/L and less than 125 nmol/L. They also needed to have adequate calcium intake (1,200 mg/day, as defined by the U.S. Institute of Medicine), or if not, they were instructed to take an appropriate calcium supplement dose.

Patients were randomized to receive 400, 4,000, or 10,000 IU/day of vitamin D3 cholecalciferol, given as 5 drops/day of liquid (Ddrops), with roughly 50 men and 50 women in each dose group.

Researchers selected the 400 IU/day dose as the comparator because the Institute of Medicine recommends a vitamin D intake of 600 IU/day for adults under age 70 years to provide the vitamin D needed for bone health. The typical Canadian diet includes 200-300 IU/day of vitamin D, so individuals would need a supplement of 400 IU/day to reach the recommended intake. The 4,000 IU/day dose is the recommended tolerable upper intake level, according to the Institute of Medicine. And the 10,000 IU/day dose is the tolerable upper intake level of vitamin D as identified in a review by Hathcock and colleagues (Am J Clin Nutr. 2007;85:6-18).

Participants underwent scans with high-resolution peripheral quantitative computed tomography (HR-pQCT) to measure total volumetric BMD at the radius and tibia at baseline, 6, 12, 24, and 36 months. Finite element analysis was used to estimate bone strength.

After 3 years, women had lost significantly more BMD at the radius after taking high-dose versus 400 IU/day of vitamin D. Losses in BMD at the tibia followed a similar trend but were smaller (Figure 1). There were no significant changes in this measure among men (Figure 2). 

There were also no significant changes in bone strength among men or women.

Biological mechanism remains to be determined

Dr. LeBoff said a “possible biological explanation” for the findings is that “women, particularly when they are younger, lose more bone than men.”

“Postmenopausal females do lose bone at an accelerated rate compared with males,” Dr. Burt agreed, “but at the time the study was designed, there was no reason to believe that high-dose vitamin D supplementation would accelerate the problem.”

“The biological mechanism of the vitamin D–related bone loss needs further investigation,” Dr. Burt added, “but there are laboratory data suggesting that supraphysiologic doses of active metabolites of vitamin D may stimulate bone resorption.”

The study was funded by the Pure North S’Energy Foundation. Dr. Burt has reported no relevant financial relationships. Disclosures for the other authors are listed with the article. Dr. LeBoff has reported receiving grants from the National Institutes of Health for the VITAL analysis.
 

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

The virtual American Society for Bone and Mineral Research 2020 annual meeting “is full of highlights,” says Lorenz Hofbauer, MD, scientific chair, but “this year you won’t lose time in the hallways to switch between the talks,” he quipped.

Nevertheless, “although we won’t be coming together face to face this year, you will have the flexibility to virtually connect with peers and colleagues from around the world,” Teresita Bellido, PhD, ASBMR president emphasized in a message to members.

Like other medical organizations, with the advent of the COVID-19 pandemic, the ASBMR had to quickly pivot to provide a virtual meeting.

The meeting will take place September 11-15 and is free for ASBMR members.  

Speaking to Medscape Medical News, Bellido and Hofbauer drew attention to some of the meeting’s major themes, key sessions, and top clinical oral abstracts.

Attendees at this year’s virtual meeting will hear the latest information on optimal sequential treatment for osteoporosis, the latest research using artificial intelligence (AI), and bone and cancer, among other topics.
 

Sequential osteoporosis treatment a recurring theme

According to Hofbauer, from Dresden Technical University, Germany, the September 13 Cutting Edge symposium entitled, “Optimizing Sequential Osteoporosis Treatment,” is not to be missed, and the topic “will be a leitmotiv [recurrent theme] for the entire meeting.”

During this session speakers will present findings from two perspectives – basic science and clinical applications – with the latter being another recurring theme at the meeting.

Bellido, from the University of Arkansas for Medical Sciences, in Little Rock, pointed out that romosozumab (Evenity, Amgen), recently approved by the US Food and Drug Administration, is an example of how basic laboratory research can lead to important new therapies.

Anabolic therapies for osteoporosis that “build up bone” include teriparatide, abaloparatide, and now romosozumab, whereas antiresorptive therapies that stop bone resorption include the bisphosphonates (alendronate, risedronate, ibandronate, and zoledronic acid) and the monoclonal antibody denosumab, Bellido explained.

As osteoporosis treatment options have expanded, the timing and sequencing of optimal therapies have become much more complex, and so this session on sequencing, as well as the September 13 Concurrent Orals session, “Issues of Long-term Treatment and Discontinuation,” is sure to spark interest.

The ASBMR/European Calcified Tissue Society debate, entitled, “A Treat to Target Approach is Helpful for Osteoporosis Management,” is also expected to be lively and generate wide interest, according to Bellido and Hofbauer.

Michael R. McClung, MD, Oregon Osteoporosis Center, Portland, will argue against the motion and Celia Gregson, PhD, University of Bristol, UK, will argue for it. Attendees will be able to vote for/against the motion before and after the debate, and the result will indicate which speaker was more persuasive.
 

Bone cancer ultimately damages other tissues

The meeting will also offer attendees a close look at bone and cancer, which is an example of how “all the homeostatic processes that occur with bone not only affect bone but also impact other tissues and organs,” said Bellido.

In other words, “what happens in bone impacts other tissues – for example, skeletal muscle, the pancreas, and even frailty and fractures.”

Theresa A. Guise, MD, from the University of Texas MD Anderson Cancer Center, in Austin, will present the Louis V. Avioli Lecture on September 11, entitled, “Cancer, Bone and Beyond: An Integrated View of the Bone Microenvironment.”

“Local events in the bone microenvironment due to cancer and cancer treatment which result in pathologic bone destruction may have widespread systemic consequences that further increase morbidity and mortality,” Hofbauer noted.

Guise “will highlight cutting-edge concepts, potential mechanisms, and therapy for bone metastases,” he said.

These concepts will also be discussed in more detail during a 2-day virtual premeeting symposium, presented on September 9 and 10 by the ASBMR along with the Cancer and Bone Society, entitled, “The Seed and Soil: Therapeutic Targets for Cancer in Bone.”

The symposium will cover tumor dormancy, imaging, adiposity in the bone tumor microenvironment, a history of bone-targeted therapies in cancer, advances in breast cancer bone metastasis, and new approaches in myeloma bone disease.

“We have evidence from breast cancer, multiple myeloma, as well as from prostate cancer,” Bellido noted, that “all those cancer cells make their home in bone and transform the bone in such a way that not only the bone is damaged but also other tissues.”

“We have skeletal muscle weakness (that is directed by the effects that occur in bone), as well as changes in the pancreas – all directed by proteins and genes in bone cells.”
 

AI, bench to bedside research

“Every field is moving towards the use of AI,” Bellido noted, and the September 11 plenary symposium entitled, “Artificial Intelligence and Precision Medicine in Musculoskeletal Health,” will shed light on how AI is being used to study bone health.

The session “will give us a glimpse of the future,” said Hofbauer.

Session topics include principles of applications to research and clinical care in bone and mineral research; how AI can help detect rare diseases; and combining genomics with medical data using AI in precision medicine for drug discovery.

“The Bench to Bedside presentation on ‘Beta Blockers and Bone’ is a great example of translational research, while the Basic Symposium on ‘Bones, Guts and Brains’ provides inspiring and thought-provoking insights into novel physiology and tempting teleology,” Hofbauer explained.

“Another fascinating Cutting Edge symposium,” he added, “is on ‘Inspiring Mechanistic Bone Stories from Around the Animal Kingdom,’ a must-see for those employing preclinical animal models.”

For more insight into early research and a research pioneer, attendees can listen to Selma Masri, PhD, from the University of California, Irvine, who will deliver the Gerald D. Aurbach Lecture entitled, “The Scientific Legacy of Paolo Sassone-Corsi: A Tour Through the Fields of Transcriptional Regulation, Epigenetics, Metabolism and Circadian Rhythms.”

Masri’s lab is dissecting how genetic disruption of the circadian clock in mouse models affects cancer, and she will discuss the work and legacy of the late Sassone-Corsi, as well as the future of the field.
 

Rare disease, fragility fractures

The ASBMR meeting will also feature the latest research into rare diseases and fragility fractures.

Rare diseases are often about “more bone or less bone,” said Bellido. “Understanding the mechanisms of these rare diseases can give us very important clues of treating the more common diseases.”

A fragility fracture is a diagnosis of osteoporosis, but most are not treated, she continued. “This is equivalent to having, for example, a heart attack and leaving the hospital after the incident was resolved and not treating it.”

“We’re trying to address this gap,” she said, and a symposium on September 14 will present some of the latest knowledge.

During the “Long-term Management of Fragility Fracture” symposium, speakers will discuss reducing mortality with antiosteoporotic treatment, new scenarios to prevent postfracture frailty, as well as fracture and postfracture management – surgeon and nursing perspectives.
 

COVID-19, nutrition, microbiome, and top 5 clinical abstracts

In addition to plenary sessions and symposiums, there are many oral abstracts and posters on important studies in the field of bone health, including, for example, a topical study of vitamin D and COVID-19.

There are also many abstracts on nutrition, the microbiome, and treating bone loss, said Bellido.

“We have a huge increase in the number of abstracts submitted from South America and Australia compared to previous years,” she noted, “and a 10% increase (from 50% to 61%) in the number of abstracts submitted by young investigators, which is crucial.”

Close to 1000 abstracts (988) were submitted, two thirds of which were clinical.

The top 5 clinical abstracts reflect important current issues in the field, said Hofbauer.

“One major theme is on long-term and sequential therapy efficacy and safety,” he said. And “burosumab is a game-changing new drug, and nutritional aspects are evergreens [perennial favorites], especially in the elderly population.”

The top 5 clinical oral abstracts at the ASBMR 2020 meeting are:

• Dairy supplementation reduces fractures and falls in institutionalized older adults: A cluster-randomized placebo-controlled trial (abstract 1022).
• Treatment with zoledronate subsequent to denosumab in osteoporosis: A randomized trial (abstract 1065).
• Efficacy of burosumab in adults with X-linked hypophosphatemia (XLH): A subgroup analysis of a randomized, double-blind, placebo-controlled, phase 3 study (abstract 1044).
• High-dose vitamin D supplementation affects bone density differently in females than males (abstract 1019).
• Bisphosphonate use and risk of atypical femoral fractures: A nationwide Danish analysis with blinded radiographic review (abstract 1061).

This article first appeared on Medscape.com.

The virtual American Society for Bone and Mineral Research 2020 annual meeting “is full of highlights,” says Lorenz Hofbauer, MD, scientific chair, but “this year you won’t lose time in the hallways to switch between the talks,” he quipped.

Nevertheless, “although we won’t be coming together face to face this year, you will have the flexibility to virtually connect with peers and colleagues from around the world,” Teresita Bellido, PhD, ASBMR president emphasized in a message to members.

Like other medical organizations, with the advent of the COVID-19 pandemic, the ASBMR had to quickly pivot to provide a virtual meeting.

The meeting will take place September 11-15 and is free for ASBMR members.  

Speaking to Medscape Medical News, Bellido and Hofbauer drew attention to some of the meeting’s major themes, key sessions, and top clinical oral abstracts.

Attendees at this year’s virtual meeting will hear the latest information on optimal sequential treatment for osteoporosis, the latest research using artificial intelligence (AI), and bone and cancer, among other topics.
 

Sequential osteoporosis treatment a recurring theme

According to Hofbauer, from Dresden Technical University, Germany, the September 13 Cutting Edge symposium entitled, “Optimizing Sequential Osteoporosis Treatment,” is not to be missed, and the topic “will be a leitmotiv [recurrent theme] for the entire meeting.”

During this session speakers will present findings from two perspectives – basic science and clinical applications – with the latter being another recurring theme at the meeting.

Bellido, from the University of Arkansas for Medical Sciences, in Little Rock, pointed out that romosozumab (Evenity, Amgen), recently approved by the US Food and Drug Administration, is an example of how basic laboratory research can lead to important new therapies.

Anabolic therapies for osteoporosis that “build up bone” include teriparatide, abaloparatide, and now romosozumab, whereas antiresorptive therapies that stop bone resorption include the bisphosphonates (alendronate, risedronate, ibandronate, and zoledronic acid) and the monoclonal antibody denosumab, Bellido explained.

As osteoporosis treatment options have expanded, the timing and sequencing of optimal therapies have become much more complex, and so this session on sequencing, as well as the September 13 Concurrent Orals session, “Issues of Long-term Treatment and Discontinuation,” is sure to spark interest.

The ASBMR/European Calcified Tissue Society debate, entitled, “A Treat to Target Approach is Helpful for Osteoporosis Management,” is also expected to be lively and generate wide interest, according to Bellido and Hofbauer.

Michael R. McClung, MD, Oregon Osteoporosis Center, Portland, will argue against the motion and Celia Gregson, PhD, University of Bristol, UK, will argue for it. Attendees will be able to vote for/against the motion before and after the debate, and the result will indicate which speaker was more persuasive.
 

Bone cancer ultimately damages other tissues

The meeting will also offer attendees a close look at bone and cancer, which is an example of how “all the homeostatic processes that occur with bone not only affect bone but also impact other tissues and organs,” said Bellido.

In other words, “what happens in bone impacts other tissues – for example, skeletal muscle, the pancreas, and even frailty and fractures.”

Theresa A. Guise, MD, from the University of Texas MD Anderson Cancer Center, in Austin, will present the Louis V. Avioli Lecture on September 11, entitled, “Cancer, Bone and Beyond: An Integrated View of the Bone Microenvironment.”

“Local events in the bone microenvironment due to cancer and cancer treatment which result in pathologic bone destruction may have widespread systemic consequences that further increase morbidity and mortality,” Hofbauer noted.

Guise “will highlight cutting-edge concepts, potential mechanisms, and therapy for bone metastases,” he said.

These concepts will also be discussed in more detail during a 2-day virtual premeeting symposium, presented on September 9 and 10 by the ASBMR along with the Cancer and Bone Society, entitled, “The Seed and Soil: Therapeutic Targets for Cancer in Bone.”

The symposium will cover tumor dormancy, imaging, adiposity in the bone tumor microenvironment, a history of bone-targeted therapies in cancer, advances in breast cancer bone metastasis, and new approaches in myeloma bone disease.

“We have evidence from breast cancer, multiple myeloma, as well as from prostate cancer,” Bellido noted, that “all those cancer cells make their home in bone and transform the bone in such a way that not only the bone is damaged but also other tissues.”

“We have skeletal muscle weakness (that is directed by the effects that occur in bone), as well as changes in the pancreas – all directed by proteins and genes in bone cells.”
 

AI, bench to bedside research

“Every field is moving towards the use of AI,” Bellido noted, and the September 11 plenary symposium entitled, “Artificial Intelligence and Precision Medicine in Musculoskeletal Health,” will shed light on how AI is being used to study bone health.

The session “will give us a glimpse of the future,” said Hofbauer.

Session topics include principles of applications to research and clinical care in bone and mineral research; how AI can help detect rare diseases; and combining genomics with medical data using AI in precision medicine for drug discovery.

“The Bench to Bedside presentation on ‘Beta Blockers and Bone’ is a great example of translational research, while the Basic Symposium on ‘Bones, Guts and Brains’ provides inspiring and thought-provoking insights into novel physiology and tempting teleology,” Hofbauer explained.

“Another fascinating Cutting Edge symposium,” he added, “is on ‘Inspiring Mechanistic Bone Stories from Around the Animal Kingdom,’ a must-see for those employing preclinical animal models.”

For more insight into early research and a research pioneer, attendees can listen to Selma Masri, PhD, from the University of California, Irvine, who will deliver the Gerald D. Aurbach Lecture entitled, “The Scientific Legacy of Paolo Sassone-Corsi: A Tour Through the Fields of Transcriptional Regulation, Epigenetics, Metabolism and Circadian Rhythms.”

Masri’s lab is dissecting how genetic disruption of the circadian clock in mouse models affects cancer, and she will discuss the work and legacy of the late Sassone-Corsi, as well as the future of the field.
 

Rare disease, fragility fractures

The ASBMR meeting will also feature the latest research into rare diseases and fragility fractures.

Rare diseases are often about “more bone or less bone,” said Bellido. “Understanding the mechanisms of these rare diseases can give us very important clues of treating the more common diseases.”

A fragility fracture is a diagnosis of osteoporosis, but most are not treated, she continued. “This is equivalent to having, for example, a heart attack and leaving the hospital after the incident was resolved and not treating it.”

“We’re trying to address this gap,” she said, and a symposium on September 14 will present some of the latest knowledge.

During the “Long-term Management of Fragility Fracture” symposium, speakers will discuss reducing mortality with antiosteoporotic treatment, new scenarios to prevent postfracture frailty, as well as fracture and postfracture management – surgeon and nursing perspectives.
 

COVID-19, nutrition, microbiome, and top 5 clinical abstracts

In addition to plenary sessions and symposiums, there are many oral abstracts and posters on important studies in the field of bone health, including, for example, a topical study of vitamin D and COVID-19.

There are also many abstracts on nutrition, the microbiome, and treating bone loss, said Bellido.

“We have a huge increase in the number of abstracts submitted from South America and Australia compared to previous years,” she noted, “and a 10% increase (from 50% to 61%) in the number of abstracts submitted by young investigators, which is crucial.”

Close to 1000 abstracts (988) were submitted, two thirds of which were clinical.

The top 5 clinical abstracts reflect important current issues in the field, said Hofbauer.

“One major theme is on long-term and sequential therapy efficacy and safety,” he said. And “burosumab is a game-changing new drug, and nutritional aspects are evergreens [perennial favorites], especially in the elderly population.”

The top 5 clinical oral abstracts at the ASBMR 2020 meeting are:

• Dairy supplementation reduces fractures and falls in institutionalized older adults: A cluster-randomized placebo-controlled trial (abstract 1022).
• Treatment with zoledronate subsequent to denosumab in osteoporosis: A randomized trial (abstract 1065).
• Efficacy of burosumab in adults with X-linked hypophosphatemia (XLH): A subgroup analysis of a randomized, double-blind, placebo-controlled, phase 3 study (abstract 1044).
• High-dose vitamin D supplementation affects bone density differently in females than males (abstract 1019).
• Bisphosphonate use and risk of atypical femoral fractures: A nationwide Danish analysis with blinded radiographic review (abstract 1061).

This article first appeared on Medscape.com.

The virtual American Society for Bone and Mineral Research 2020 annual meeting “is full of highlights,” says Lorenz Hofbauer, MD, scientific chair, but “this year you won’t lose time in the hallways to switch between the talks,” he quipped.

Nevertheless, “although we won’t be coming together face to face this year, you will have the flexibility to virtually connect with peers and colleagues from around the world,” Teresita Bellido, PhD, ASBMR president emphasized in a message to members.

Like other medical organizations, with the advent of the COVID-19 pandemic, the ASBMR had to quickly pivot to provide a virtual meeting.

The meeting will take place September 11-15 and is free for ASBMR members.  

Speaking to Medscape Medical News, Bellido and Hofbauer drew attention to some of the meeting’s major themes, key sessions, and top clinical oral abstracts.

Attendees at this year’s virtual meeting will hear the latest information on optimal sequential treatment for osteoporosis, the latest research using artificial intelligence (AI), and bone and cancer, among other topics.
 

Sequential osteoporosis treatment a recurring theme

According to Hofbauer, from Dresden Technical University, Germany, the September 13 Cutting Edge symposium entitled, “Optimizing Sequential Osteoporosis Treatment,” is not to be missed, and the topic “will be a leitmotiv [recurrent theme] for the entire meeting.”

During this session speakers will present findings from two perspectives – basic science and clinical applications – with the latter being another recurring theme at the meeting.

Bellido, from the University of Arkansas for Medical Sciences, in Little Rock, pointed out that romosozumab (Evenity, Amgen), recently approved by the US Food and Drug Administration, is an example of how basic laboratory research can lead to important new therapies.

Anabolic therapies for osteoporosis that “build up bone” include teriparatide, abaloparatide, and now romosozumab, whereas antiresorptive therapies that stop bone resorption include the bisphosphonates (alendronate, risedronate, ibandronate, and zoledronic acid) and the monoclonal antibody denosumab, Bellido explained.

As osteoporosis treatment options have expanded, the timing and sequencing of optimal therapies have become much more complex, and so this session on sequencing, as well as the September 13 Concurrent Orals session, “Issues of Long-term Treatment and Discontinuation,” is sure to spark interest.

The ASBMR/European Calcified Tissue Society debate, entitled, “A Treat to Target Approach is Helpful for Osteoporosis Management,” is also expected to be lively and generate wide interest, according to Bellido and Hofbauer.

Michael R. McClung, MD, Oregon Osteoporosis Center, Portland, will argue against the motion and Celia Gregson, PhD, University of Bristol, UK, will argue for it. Attendees will be able to vote for/against the motion before and after the debate, and the result will indicate which speaker was more persuasive.
 

Bone cancer ultimately damages other tissues

The meeting will also offer attendees a close look at bone and cancer, which is an example of how “all the homeostatic processes that occur with bone not only affect bone but also impact other tissues and organs,” said Bellido.

In other words, “what happens in bone impacts other tissues – for example, skeletal muscle, the pancreas, and even frailty and fractures.”

Theresa A. Guise, MD, from the University of Texas MD Anderson Cancer Center, in Austin, will present the Louis V. Avioli Lecture on September 11, entitled, “Cancer, Bone and Beyond: An Integrated View of the Bone Microenvironment.”

“Local events in the bone microenvironment due to cancer and cancer treatment which result in pathologic bone destruction may have widespread systemic consequences that further increase morbidity and mortality,” Hofbauer noted.

Guise “will highlight cutting-edge concepts, potential mechanisms, and therapy for bone metastases,” he said.

These concepts will also be discussed in more detail during a 2-day virtual premeeting symposium, presented on September 9 and 10 by the ASBMR along with the Cancer and Bone Society, entitled, “The Seed and Soil: Therapeutic Targets for Cancer in Bone.”

The symposium will cover tumor dormancy, imaging, adiposity in the bone tumor microenvironment, a history of bone-targeted therapies in cancer, advances in breast cancer bone metastasis, and new approaches in myeloma bone disease.

“We have evidence from breast cancer, multiple myeloma, as well as from prostate cancer,” Bellido noted, that “all those cancer cells make their home in bone and transform the bone in such a way that not only the bone is damaged but also other tissues.”

“We have skeletal muscle weakness (that is directed by the effects that occur in bone), as well as changes in the pancreas – all directed by proteins and genes in bone cells.”
 

AI, bench to bedside research

“Every field is moving towards the use of AI,” Bellido noted, and the September 11 plenary symposium entitled, “Artificial Intelligence and Precision Medicine in Musculoskeletal Health,” will shed light on how AI is being used to study bone health.

The session “will give us a glimpse of the future,” said Hofbauer.

Session topics include principles of applications to research and clinical care in bone and mineral research; how AI can help detect rare diseases; and combining genomics with medical data using AI in precision medicine for drug discovery.

“The Bench to Bedside presentation on ‘Beta Blockers and Bone’ is a great example of translational research, while the Basic Symposium on ‘Bones, Guts and Brains’ provides inspiring and thought-provoking insights into novel physiology and tempting teleology,” Hofbauer explained.

“Another fascinating Cutting Edge symposium,” he added, “is on ‘Inspiring Mechanistic Bone Stories from Around the Animal Kingdom,’ a must-see for those employing preclinical animal models.”

For more insight into early research and a research pioneer, attendees can listen to Selma Masri, PhD, from the University of California, Irvine, who will deliver the Gerald D. Aurbach Lecture entitled, “The Scientific Legacy of Paolo Sassone-Corsi: A Tour Through the Fields of Transcriptional Regulation, Epigenetics, Metabolism and Circadian Rhythms.”

Masri’s lab is dissecting how genetic disruption of the circadian clock in mouse models affects cancer, and she will discuss the work and legacy of the late Sassone-Corsi, as well as the future of the field.
 

Rare disease, fragility fractures

The ASBMR meeting will also feature the latest research into rare diseases and fragility fractures.

Rare diseases are often about “more bone or less bone,” said Bellido. “Understanding the mechanisms of these rare diseases can give us very important clues of treating the more common diseases.”

A fragility fracture is a diagnosis of osteoporosis, but most are not treated, she continued. “This is equivalent to having, for example, a heart attack and leaving the hospital after the incident was resolved and not treating it.”

“We’re trying to address this gap,” she said, and a symposium on September 14 will present some of the latest knowledge.

During the “Long-term Management of Fragility Fracture” symposium, speakers will discuss reducing mortality with antiosteoporotic treatment, new scenarios to prevent postfracture frailty, as well as fracture and postfracture management – surgeon and nursing perspectives.
 

COVID-19, nutrition, microbiome, and top 5 clinical abstracts

In addition to plenary sessions and symposiums, there are many oral abstracts and posters on important studies in the field of bone health, including, for example, a topical study of vitamin D and COVID-19.

There are also many abstracts on nutrition, the microbiome, and treating bone loss, said Bellido.

“We have a huge increase in the number of abstracts submitted from South America and Australia compared to previous years,” she noted, “and a 10% increase (from 50% to 61%) in the number of abstracts submitted by young investigators, which is crucial.”

Close to 1000 abstracts (988) were submitted, two thirds of which were clinical.

The top 5 clinical abstracts reflect important current issues in the field, said Hofbauer.

“One major theme is on long-term and sequential therapy efficacy and safety,” he said. And “burosumab is a game-changing new drug, and nutritional aspects are evergreens [perennial favorites], especially in the elderly population.”

The top 5 clinical oral abstracts at the ASBMR 2020 meeting are:

• Dairy supplementation reduces fractures and falls in institutionalized older adults: A cluster-randomized placebo-controlled trial (abstract 1022).
• Treatment with zoledronate subsequent to denosumab in osteoporosis: A randomized trial (abstract 1065).
• Efficacy of burosumab in adults with X-linked hypophosphatemia (XLH): A subgroup analysis of a randomized, double-blind, placebo-controlled, phase 3 study (abstract 1044).
• High-dose vitamin D supplementation affects bone density differently in females than males (abstract 1019).
• Bisphosphonate use and risk of atypical femoral fractures: A nationwide Danish analysis with blinded radiographic review (abstract 1061).

This article first appeared on Medscape.com.

A new study has found that older patients who test positive for the cytotoxin associated gene-A (CagA) strain of Helicobacter pylori may be more at risk of both osteoporosis and fractures.

Patho/Wikimedia Commons/CC BY-SA 3.0

“Further studies will be required to replicate these findings in other cohorts and to better clarify the underlying pathogenetic mechanisms leading to increased bone fragility in subjects infected by CagA-positive H. pylori strains,” wrote Luigi Gennari, MD, PhD, of the University of Siena (Italy), and coauthors. The study was published in the Journal of Bone and Mineral Research.

To determine the effects of H. pylori on bone health and potential fracture risk, the researchers launched a population-based cohort study of 1,149 adults between the ages of 50 and 80 in Siena. The cohort comprised 174 males with an average (SD) age of 65.9 (plus or minus 6 years) and 975 females with an average age of 62.5 (plus or minus 6 years). All subjects were examined for H. pylori antibodies, and those who were infected were also examined for anti-CagA serum antibodies. As blood was sampled, bone mineral density (BMD) of the lumbar spine, femoral neck, total hip, and total body was measured via dual-energy x-ray absorptiometry.

In total, 53% of male participants and 49% of female participants tested positive for H. pylori, with CagA-positive strains found in 27% of males and 26% of females. No differences in infection rates were discovered in regard to socioeconomic status, age, weight, or height. Patients with normal BMD (45%), osteoporosis (51%), or osteopenia (49%) had similar prevalence of H. pylori infection, but CagA-positive strains were more frequently found in osteoporotic (30%) and osteopenic (26%) patients, compared to patients with normal BMD (21%, P < .01). CagA-positive female patients also had lower lumbar (0.950 g/cm²) and femoral (0.795 g/cm²) BMD, compared to CagA-negative (0.987 and 0.813 g/cm²) or H. pylori-negative women (0.997 and 0.821 g/cm²), respectively.

After an average follow-up period of 11.8 years, 199 nontraumatic fractures (72 vertebral and 127 nonvertebral) had occurred in 158 participants. Patients with CagA-positive strains of H. pylori had significantly increased risk of a clinical vertebral fracture (hazard ratio [HR], 5.27; 95% confidence interval, 2.23-12.63; P < .0001) or a nonvertebral incident fracture (HR, 2.09; 95% CI, 1.27-2.46; P < .01), compared to patients without H. pylori. After adjustment for age, sex, and body mass index, the risk among CagA-positive patients remained similarly significantly elevated for both vertebral (aHR, 4.78; 95% CI, 1.99-11.47; P < .0001) and nonvertebral fractures (aHR, 2.04; 95% CI, 1.22-3.41; P < .01).

The authors acknowledged their study’s limitations, including a cohort that was notably low in male participants, an inability to assess the effects of eradicating H. pylori on bone, and uncertainty as to which specific effects of H. pylori infection increase the risk of osteoporosis or fracture. Along those lines, they noted that an association between serum CagA antibody titer and gastric mucosal inflammation could lead to malabsorption of calcium, hypothesizing that antibody titer rather than antibody positivity “might be a more relevant marker for assessing the risk of bone fragility in patients affected by H. pylori infection.”

The study was supported in part by a grant from the Italian Association for Osteoporosis. The authors reported no potential conflicts of interest.

SOURCE: Gennari L et al. J Bone Miner Res. 2020 Aug 13. doi: 10.1002/jbmr.4162.

A new study has found that older patients who test positive for the cytotoxin associated gene-A (CagA) strain of Helicobacter pylori may be more at risk of both osteoporosis and fractures.

Patho/Wikimedia Commons/CC BY-SA 3.0

“Further studies will be required to replicate these findings in other cohorts and to better clarify the underlying pathogenetic mechanisms leading to increased bone fragility in subjects infected by CagA-positive H. pylori strains,” wrote Luigi Gennari, MD, PhD, of the University of Siena (Italy), and coauthors. The study was published in the Journal of Bone and Mineral Research.

To determine the effects of H. pylori on bone health and potential fracture risk, the researchers launched a population-based cohort study of 1,149 adults between the ages of 50 and 80 in Siena. The cohort comprised 174 males with an average (SD) age of 65.9 (plus or minus 6 years) and 975 females with an average age of 62.5 (plus or minus 6 years). All subjects were examined for H. pylori antibodies, and those who were infected were also examined for anti-CagA serum antibodies. As blood was sampled, bone mineral density (BMD) of the lumbar spine, femoral neck, total hip, and total body was measured via dual-energy x-ray absorptiometry.

In total, 53% of male participants and 49% of female participants tested positive for H. pylori, with CagA-positive strains found in 27% of males and 26% of females. No differences in infection rates were discovered in regard to socioeconomic status, age, weight, or height. Patients with normal BMD (45%), osteoporosis (51%), or osteopenia (49%) had similar prevalence of H. pylori infection, but CagA-positive strains were more frequently found in osteoporotic (30%) and osteopenic (26%) patients, compared to patients with normal BMD (21%, P < .01). CagA-positive female patients also had lower lumbar (0.950 g/cm²) and femoral (0.795 g/cm²) BMD, compared to CagA-negative (0.987 and 0.813 g/cm²) or H. pylori-negative women (0.997 and 0.821 g/cm²), respectively.

After an average follow-up period of 11.8 years, 199 nontraumatic fractures (72 vertebral and 127 nonvertebral) had occurred in 158 participants. Patients with CagA-positive strains of H. pylori had significantly increased risk of a clinical vertebral fracture (hazard ratio [HR], 5.27; 95% confidence interval, 2.23-12.63; P < .0001) or a nonvertebral incident fracture (HR, 2.09; 95% CI, 1.27-2.46; P < .01), compared to patients without H. pylori. After adjustment for age, sex, and body mass index, the risk among CagA-positive patients remained similarly significantly elevated for both vertebral (aHR, 4.78; 95% CI, 1.99-11.47; P < .0001) and nonvertebral fractures (aHR, 2.04; 95% CI, 1.22-3.41; P < .01).

The authors acknowledged their study’s limitations, including a cohort that was notably low in male participants, an inability to assess the effects of eradicating H. pylori on bone, and uncertainty as to which specific effects of H. pylori infection increase the risk of osteoporosis or fracture. Along those lines, they noted that an association between serum CagA antibody titer and gastric mucosal inflammation could lead to malabsorption of calcium, hypothesizing that antibody titer rather than antibody positivity “might be a more relevant marker for assessing the risk of bone fragility in patients affected by H. pylori infection.”

The study was supported in part by a grant from the Italian Association for Osteoporosis. The authors reported no potential conflicts of interest.

SOURCE: Gennari L et al. J Bone Miner Res. 2020 Aug 13. doi: 10.1002/jbmr.4162.

A new study has found that older patients who test positive for the cytotoxin associated gene-A (CagA) strain of Helicobacter pylori may be more at risk of both osteoporosis and fractures.

Patho/Wikimedia Commons/CC BY-SA 3.0

“Further studies will be required to replicate these findings in other cohorts and to better clarify the underlying pathogenetic mechanisms leading to increased bone fragility in subjects infected by CagA-positive H. pylori strains,” wrote Luigi Gennari, MD, PhD, of the University of Siena (Italy), and coauthors. The study was published in the Journal of Bone and Mineral Research.

To determine the effects of H. pylori on bone health and potential fracture risk, the researchers launched a population-based cohort study of 1,149 adults between the ages of 50 and 80 in Siena. The cohort comprised 174 males with an average (SD) age of 65.9 (plus or minus 6 years) and 975 females with an average age of 62.5 (plus or minus 6 years). All subjects were examined for H. pylori antibodies, and those who were infected were also examined for anti-CagA serum antibodies. As blood was sampled, bone mineral density (BMD) of the lumbar spine, femoral neck, total hip, and total body was measured via dual-energy x-ray absorptiometry.

In total, 53% of male participants and 49% of female participants tested positive for H. pylori, with CagA-positive strains found in 27% of males and 26% of females. No differences in infection rates were discovered in regard to socioeconomic status, age, weight, or height. Patients with normal BMD (45%), osteoporosis (51%), or osteopenia (49%) had similar prevalence of H. pylori infection, but CagA-positive strains were more frequently found in osteoporotic (30%) and osteopenic (26%) patients, compared to patients with normal BMD (21%, P < .01). CagA-positive female patients also had lower lumbar (0.950 g/cm²) and femoral (0.795 g/cm²) BMD, compared to CagA-negative (0.987 and 0.813 g/cm²) or H. pylori-negative women (0.997 and 0.821 g/cm²), respectively.

After an average follow-up period of 11.8 years, 199 nontraumatic fractures (72 vertebral and 127 nonvertebral) had occurred in 158 participants. Patients with CagA-positive strains of H. pylori had significantly increased risk of a clinical vertebral fracture (hazard ratio [HR], 5.27; 95% confidence interval, 2.23-12.63; P < .0001) or a nonvertebral incident fracture (HR, 2.09; 95% CI, 1.27-2.46; P < .01), compared to patients without H. pylori. After adjustment for age, sex, and body mass index, the risk among CagA-positive patients remained similarly significantly elevated for both vertebral (aHR, 4.78; 95% CI, 1.99-11.47; P < .0001) and nonvertebral fractures (aHR, 2.04; 95% CI, 1.22-3.41; P < .01).

The authors acknowledged their study’s limitations, including a cohort that was notably low in male participants, an inability to assess the effects of eradicating H. pylori on bone, and uncertainty as to which specific effects of H. pylori infection increase the risk of osteoporosis or fracture. Along those lines, they noted that an association between serum CagA antibody titer and gastric mucosal inflammation could lead to malabsorption of calcium, hypothesizing that antibody titer rather than antibody positivity “might be a more relevant marker for assessing the risk of bone fragility in patients affected by H. pylori infection.”

The study was supported in part by a grant from the Italian Association for Osteoporosis. The authors reported no potential conflicts of interest.

SOURCE: Gennari L et al. J Bone Miner Res. 2020 Aug 13. doi: 10.1002/jbmr.4162.

The latest findings regarding the risk for atypical femur fracture (AFF) with use of bisphosphonates for osteoporosis show a significant increase in risk when treatment extends beyond 5 years. The risk is notably higher risk among Asian women, compared with White women. However, the benefits in fracture reduction still appear to far outweigh the risk for AFF.

The research, published in the New England Journal of Medicine, importantly adds to findings from smaller studies by showing effects in a population of nearly 200,000 women in a diverse cohort, said Angela M. Cheung, MD, PhD.

“This study answers some important questions – Kaiser Permanente Southern California is a large health maintenance organization with a diverse racial population,” said Dr. Cheung, director of the Center of Excellence in Skeletal Health Assessment and osteoporosis program at the University of Toronto.

“This is the first study that included a diverse population to definitively show that Asians are at a much higher risk of atypical femur fractures than Caucasians,” she emphasized.

Although AFFs are rare, concerns about them remain pressing in the treatment of osteoporosis, Dr. Cheung noted. “This is a big concern for clinicians – they want to do no harm.”
 

Risk for AFF increases with longer duration of bisphosphonate use

For the study, Dennis M. Black, PhD, of the departments of epidemiology and biostatistics and orthopedic surgery at the University of California, San Francisco, and colleagues identified women aged 50 years or older enrolled in the Kaiser Permanente Southern California system who were treated with bisphosphonates and were followed from January 2007 to November 2017.

Among the 196,129 women identified in the study, 277 AFFs occurred.

After multivariate adjustment, compared with those treated for less than 3 months, for women who were treated for 3-5 years, the hazard ratio for experiencing an AFF was 8.86. For therapy of 5-8 years, the HR increased to 19.88, and for those treated with bisphosphonates for 8 years or longer, the HR was 43.51.

The risk for AFF declined quickly upon bisphosphonate discontinuation; compared with current users, the HR dropped to 0.52 within 3-15 months after the last bisphosphonate use. It declined to 0.26 at more than 4 years after discontinuation.

The risk for AFF with bisphosphonate use was higher for Asian women than for White women (HR, 4.84); this did not apply to any other ethnic groups (HR, 0.99).

Other risk factors for AFF included shorter height (HR, 1.28 per 5-cm decrement), greater weight (HR, 1.15 per 5-kg increment), and glucocorticoid use (HR, 2.28 for glucocorticoid use of 1 or more years).

Among White women, the number of fractures prevented with bisphosphonate use far outweighed the risk for bisphosphonate-associated AFFs.

For example, among White women, during a 3-year treatment period, there were two bisphosphonate-associated AFFs, whereas 149 hip fractures and 541 clinical fractures were prevented, the authors wrote.

After 5 years, there were eight AFFs, but 286 hip fractures and 859 clinical fractures were prevented.

Although the risk-benefit ratio among Asian women still favored prevention of fractures, the difference was less pronounced – eight bisphosphonate-associated AFFs had occurred at 3 years, whereas 91 hip fractures and 330 clinical fractures were prevented.

The authors noted that previous studies have also shown Asian women to be at a disproportionately higher risk for AFF.

An earlier Kaiser Permanente Southern California case series showed that 49% of 142 AFFs occurred in Asian patients, despite the fact that those patients made up only 10% of the study population.

Various factors could cause higher risk in Asian women

The reasons for the increased risk among Asian women are likely multifactorial and could include greater medication adherence among Asian women, genetic differences in drug metabolism and bone turnover, and, notably, increased lateral stress caused by bowed Asian femora, the authors speculated.

Further questions include whether the risk is limited to Asians living outside of Asia and whether cultural differences in diet or physical activity are risk factors, they added.

“At this early stage, further research into the cause of the increased risk among women of Asian ancestry is warranted,” they wrote.

Although the risk for AFF may be higher among Asian women, the incidence of hip and other osteoporotic fractures is lower among Asians as well as other non-White persons, compared with White persons, they added.

The findings have important implications in how clinicians should discuss treatment options with different patient groups, Dr. Cheung said.

“I think this is one of the key findings of the study,” she added. “In this day and age of personalized medicine, we need to keep the individual patient in mind, and that includes their racial/ethnic background, genetic characteristics, sex, medical conditions and medications, etc. So it is important for physicians to pay attention to this. The risk-benefit ratio of these drugs for Asians will be quite different, compared to Caucasians.”
 

No link between traditional fracture risk factors and AFF, study shows

Interestingly, although older age, previous fractures, and lower bone mineral density are key risk factors for hip and other osteoporotic fractures in the general population, they do not significantly increase the risk for AFF with bisphosphonate use, the study also showed.

“In fact, the oldest women in our cohort, who are at highest risk for hip and other fractures, were at lowest risk for AFF,” the authors wrote.

The collective findings “add to the risk-benefit balance of bisphosphonate treatment in these populations and could directly affect decisions regarding treatment initiation and duration.”

Notable limitations of the study include the fact that most women were treated with one particular bisphosphonate, alendronate, and that other bisphosphonates were underrepresented, Dr. Cheung said.

“This study examined bisphosphonate therapy, but the vast majority of the women were exposed to alendronate, so whether women on risedronate or other bisphosphonates have similar risks is unclear,” she observed.

“In addition, because they can only capture bisphosphonate use using their database, any bisphosphonate exposure prior to joining Kaiser Permanente will not be captured. So the study may underestimate the total cumulative duration of bisphosphonate use,” she added.

The study received support from Kaiser Permanente and discretionary funds from the University of California, San Francisco. The study began with a pilot grant from Merck Sharp & Dohme, which had no role in the conduct of the study. Dr. Cheung has served as a consultant for Amgen. She chaired and led the 2019 International Society for Clinical Densitometry Position Development Conference on Detection of Atypical Femur Fractures and currently is on the Osteoporosis Canada Guidelines Committee.

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

The latest findings regarding the risk for atypical femur fracture (AFF) with use of bisphosphonates for osteoporosis show a significant increase in risk when treatment extends beyond 5 years. The risk is notably higher risk among Asian women, compared with White women. However, the benefits in fracture reduction still appear to far outweigh the risk for AFF.

The research, published in the New England Journal of Medicine, importantly adds to findings from smaller studies by showing effects in a population of nearly 200,000 women in a diverse cohort, said Angela M. Cheung, MD, PhD.

“This study answers some important questions – Kaiser Permanente Southern California is a large health maintenance organization with a diverse racial population,” said Dr. Cheung, director of the Center of Excellence in Skeletal Health Assessment and osteoporosis program at the University of Toronto.

“This is the first study that included a diverse population to definitively show that Asians are at a much higher risk of atypical femur fractures than Caucasians,” she emphasized.

Although AFFs are rare, concerns about them remain pressing in the treatment of osteoporosis, Dr. Cheung noted. “This is a big concern for clinicians – they want to do no harm.”
 

Risk for AFF increases with longer duration of bisphosphonate use

For the study, Dennis M. Black, PhD, of the departments of epidemiology and biostatistics and orthopedic surgery at the University of California, San Francisco, and colleagues identified women aged 50 years or older enrolled in the Kaiser Permanente Southern California system who were treated with bisphosphonates and were followed from January 2007 to November 2017.

Among the 196,129 women identified in the study, 277 AFFs occurred.

After multivariate adjustment, compared with those treated for less than 3 months, for women who were treated for 3-5 years, the hazard ratio for experiencing an AFF was 8.86. For therapy of 5-8 years, the HR increased to 19.88, and for those treated with bisphosphonates for 8 years or longer, the HR was 43.51.

The risk for AFF declined quickly upon bisphosphonate discontinuation; compared with current users, the HR dropped to 0.52 within 3-15 months after the last bisphosphonate use. It declined to 0.26 at more than 4 years after discontinuation.

The risk for AFF with bisphosphonate use was higher for Asian women than for White women (HR, 4.84); this did not apply to any other ethnic groups (HR, 0.99).

Other risk factors for AFF included shorter height (HR, 1.28 per 5-cm decrement), greater weight (HR, 1.15 per 5-kg increment), and glucocorticoid use (HR, 2.28 for glucocorticoid use of 1 or more years).

Among White women, the number of fractures prevented with bisphosphonate use far outweighed the risk for bisphosphonate-associated AFFs.

For example, among White women, during a 3-year treatment period, there were two bisphosphonate-associated AFFs, whereas 149 hip fractures and 541 clinical fractures were prevented, the authors wrote.

After 5 years, there were eight AFFs, but 286 hip fractures and 859 clinical fractures were prevented.

Although the risk-benefit ratio among Asian women still favored prevention of fractures, the difference was less pronounced – eight bisphosphonate-associated AFFs had occurred at 3 years, whereas 91 hip fractures and 330 clinical fractures were prevented.

The authors noted that previous studies have also shown Asian women to be at a disproportionately higher risk for AFF.

An earlier Kaiser Permanente Southern California case series showed that 49% of 142 AFFs occurred in Asian patients, despite the fact that those patients made up only 10% of the study population.

Various factors could cause higher risk in Asian women

The reasons for the increased risk among Asian women are likely multifactorial and could include greater medication adherence among Asian women, genetic differences in drug metabolism and bone turnover, and, notably, increased lateral stress caused by bowed Asian femora, the authors speculated.

Further questions include whether the risk is limited to Asians living outside of Asia and whether cultural differences in diet or physical activity are risk factors, they added.

“At this early stage, further research into the cause of the increased risk among women of Asian ancestry is warranted,” they wrote.

Although the risk for AFF may be higher among Asian women, the incidence of hip and other osteoporotic fractures is lower among Asians as well as other non-White persons, compared with White persons, they added.

The findings have important implications in how clinicians should discuss treatment options with different patient groups, Dr. Cheung said.

“I think this is one of the key findings of the study,” she added. “In this day and age of personalized medicine, we need to keep the individual patient in mind, and that includes their racial/ethnic background, genetic characteristics, sex, medical conditions and medications, etc. So it is important for physicians to pay attention to this. The risk-benefit ratio of these drugs for Asians will be quite different, compared to Caucasians.”
 

No link between traditional fracture risk factors and AFF, study shows

Interestingly, although older age, previous fractures, and lower bone mineral density are key risk factors for hip and other osteoporotic fractures in the general population, they do not significantly increase the risk for AFF with bisphosphonate use, the study also showed.

“In fact, the oldest women in our cohort, who are at highest risk for hip and other fractures, were at lowest risk for AFF,” the authors wrote.

The collective findings “add to the risk-benefit balance of bisphosphonate treatment in these populations and could directly affect decisions regarding treatment initiation and duration.”

Notable limitations of the study include the fact that most women were treated with one particular bisphosphonate, alendronate, and that other bisphosphonates were underrepresented, Dr. Cheung said.

“This study examined bisphosphonate therapy, but the vast majority of the women were exposed to alendronate, so whether women on risedronate or other bisphosphonates have similar risks is unclear,” she observed.

“In addition, because they can only capture bisphosphonate use using their database, any bisphosphonate exposure prior to joining Kaiser Permanente will not be captured. So the study may underestimate the total cumulative duration of bisphosphonate use,” she added.

The study received support from Kaiser Permanente and discretionary funds from the University of California, San Francisco. The study began with a pilot grant from Merck Sharp & Dohme, which had no role in the conduct of the study. Dr. Cheung has served as a consultant for Amgen. She chaired and led the 2019 International Society for Clinical Densitometry Position Development Conference on Detection of Atypical Femur Fractures and currently is on the Osteoporosis Canada Guidelines Committee.

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

The latest findings regarding the risk for atypical femur fracture (AFF) with use of bisphosphonates for osteoporosis show a significant increase in risk when treatment extends beyond 5 years. The risk is notably higher risk among Asian women, compared with White women. However, the benefits in fracture reduction still appear to far outweigh the risk for AFF.

The research, published in the New England Journal of Medicine, importantly adds to findings from smaller studies by showing effects in a population of nearly 200,000 women in a diverse cohort, said Angela M. Cheung, MD, PhD.

“This study answers some important questions – Kaiser Permanente Southern California is a large health maintenance organization with a diverse racial population,” said Dr. Cheung, director of the Center of Excellence in Skeletal Health Assessment and osteoporosis program at the University of Toronto.

“This is the first study that included a diverse population to definitively show that Asians are at a much higher risk of atypical femur fractures than Caucasians,” she emphasized.

Although AFFs are rare, concerns about them remain pressing in the treatment of osteoporosis, Dr. Cheung noted. “This is a big concern for clinicians – they want to do no harm.”
 

Risk for AFF increases with longer duration of bisphosphonate use

For the study, Dennis M. Black, PhD, of the departments of epidemiology and biostatistics and orthopedic surgery at the University of California, San Francisco, and colleagues identified women aged 50 years or older enrolled in the Kaiser Permanente Southern California system who were treated with bisphosphonates and were followed from January 2007 to November 2017.

Among the 196,129 women identified in the study, 277 AFFs occurred.

After multivariate adjustment, compared with those treated for less than 3 months, for women who were treated for 3-5 years, the hazard ratio for experiencing an AFF was 8.86. For therapy of 5-8 years, the HR increased to 19.88, and for those treated with bisphosphonates for 8 years or longer, the HR was 43.51.

The risk for AFF declined quickly upon bisphosphonate discontinuation; compared with current users, the HR dropped to 0.52 within 3-15 months after the last bisphosphonate use. It declined to 0.26 at more than 4 years after discontinuation.

The risk for AFF with bisphosphonate use was higher for Asian women than for White women (HR, 4.84); this did not apply to any other ethnic groups (HR, 0.99).

Other risk factors for AFF included shorter height (HR, 1.28 per 5-cm decrement), greater weight (HR, 1.15 per 5-kg increment), and glucocorticoid use (HR, 2.28 for glucocorticoid use of 1 or more years).

Among White women, the number of fractures prevented with bisphosphonate use far outweighed the risk for bisphosphonate-associated AFFs.

For example, among White women, during a 3-year treatment period, there were two bisphosphonate-associated AFFs, whereas 149 hip fractures and 541 clinical fractures were prevented, the authors wrote.

After 5 years, there were eight AFFs, but 286 hip fractures and 859 clinical fractures were prevented.

Although the risk-benefit ratio among Asian women still favored prevention of fractures, the difference was less pronounced – eight bisphosphonate-associated AFFs had occurred at 3 years, whereas 91 hip fractures and 330 clinical fractures were prevented.

The authors noted that previous studies have also shown Asian women to be at a disproportionately higher risk for AFF.

An earlier Kaiser Permanente Southern California case series showed that 49% of 142 AFFs occurred in Asian patients, despite the fact that those patients made up only 10% of the study population.

Various factors could cause higher risk in Asian women

The reasons for the increased risk among Asian women are likely multifactorial and could include greater medication adherence among Asian women, genetic differences in drug metabolism and bone turnover, and, notably, increased lateral stress caused by bowed Asian femora, the authors speculated.

Further questions include whether the risk is limited to Asians living outside of Asia and whether cultural differences in diet or physical activity are risk factors, they added.

“At this early stage, further research into the cause of the increased risk among women of Asian ancestry is warranted,” they wrote.

Although the risk for AFF may be higher among Asian women, the incidence of hip and other osteoporotic fractures is lower among Asians as well as other non-White persons, compared with White persons, they added.

The findings have important implications in how clinicians should discuss treatment options with different patient groups, Dr. Cheung said.

“I think this is one of the key findings of the study,” she added. “In this day and age of personalized medicine, we need to keep the individual patient in mind, and that includes their racial/ethnic background, genetic characteristics, sex, medical conditions and medications, etc. So it is important for physicians to pay attention to this. The risk-benefit ratio of these drugs for Asians will be quite different, compared to Caucasians.”
 

No link between traditional fracture risk factors and AFF, study shows

Interestingly, although older age, previous fractures, and lower bone mineral density are key risk factors for hip and other osteoporotic fractures in the general population, they do not significantly increase the risk for AFF with bisphosphonate use, the study also showed.

“In fact, the oldest women in our cohort, who are at highest risk for hip and other fractures, were at lowest risk for AFF,” the authors wrote.

The collective findings “add to the risk-benefit balance of bisphosphonate treatment in these populations and could directly affect decisions regarding treatment initiation and duration.”

Notable limitations of the study include the fact that most women were treated with one particular bisphosphonate, alendronate, and that other bisphosphonates were underrepresented, Dr. Cheung said.

“This study examined bisphosphonate therapy, but the vast majority of the women were exposed to alendronate, so whether women on risedronate or other bisphosphonates have similar risks is unclear,” she observed.

“In addition, because they can only capture bisphosphonate use using their database, any bisphosphonate exposure prior to joining Kaiser Permanente will not be captured. So the study may underestimate the total cumulative duration of bisphosphonate use,” she added.

The study received support from Kaiser Permanente and discretionary funds from the University of California, San Francisco. The study began with a pilot grant from Merck Sharp & Dohme, which had no role in the conduct of the study. Dr. Cheung has served as a consultant for Amgen. She chaired and led the 2019 International Society for Clinical Densitometry Position Development Conference on Detection of Atypical Femur Fractures and currently is on the Osteoporosis Canada Guidelines Committee.

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

The combination of sodium-glucose transporter-2 (SGLT-2) inhibitors and metformin is not associated with an increase in fracture risk among patients with type 2 diabetes (T2D), according to a new meta-analysis of 25 randomized, controlled trials.

Researchers at The Second Clinical College of Dalian Medical University in Jiangsu, China, compared fracture risk associated with the metformin/SLGT2 combination to metformin alone as well as other T2D therapeutics, and found no differences in risk. The study was published online Aug. 11 in Osteoporosis International.

T2D is associated with an increased risk of fracture, though causative mechanisms remain uncertain. Some lines of evidence suggest multiple factors may contribute to fractures, including hyperglycemia, oxidative stress, toxic effects of advanced glycosylation end-products, altered insulin levels, and treatment-induced hypoglycemia, as well as an association between T2D and increased risk of falls.

Antidiabetes drugs can have positive or negative effects on bone. thiazolidinediones, insulin, and sulfonylureas may increase risk of fractures, while dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-2 (GLP-2) receptor agonists may be protective. Metformin may also reduce fracture risk.

SGLT-2 inhibitors interrupt glucose reabsorption in the kidney, leading to improved glycemic control. Other benefits include improved renal and cardiovascular outcomes, weight loss, and reduced blood pressure, liver fat, and serum uric acid levels.

These properties have made SGLT-2 inhibitors combined with metformin an important therapy for patients at high risk of atherosclerotic disease, or who have heart failure or chronic kidney disease.

But SGLT-2 inhibition increases osmotic diuresis, and this could alter the mineral balance within bone. Some studies also showed that SGLT-2 inhibitors led to changes in bone turnover markers, bone mineral density, and bone microarchitecture. Observational studies of the SGLT-2 inhibitor canagliflozin found associations with a higher rate of fracture risk in patients taking the drug.

Such studies carry the risk of confounding factors, so the researchers took advantage of the fact that many recent clinical trials have examined the impact of SGLT-2 inhibitors on T2D. They pooled data from 25 clinical trials with a total of 19,500 participants, 9,662 of whom received SGLT-2 inhibitors plus metformin; 9,838 received other active comparators.

The fracture rate was 0.91% in the SGLT-2 inhibitors/metformin group, and 0.80% among controls (odds ratio, 0.97; 95% CI, 0.71-1.32), with no heterogeneity. Metformin alone was not associated with a change in fracture rate (OR, 0.95; 95% CI, 0.44-2.08), nor were other forms of diabetes control (OR, 0.95; 95% CI, 0.69-1.31).

There were some differences in fracture risk among SGLT-2 inhibitors when studied individually, though none differed significantly from controls. The highest risk was associated with the canagliflozin/metformin (OR, 2.19; 95% CI, 0.66-7.27), followed by dapagliflozin/metformin (OR, 0.91; 95% CI, 0.50-1.64), empagliflozin/metformin (OR, 0.94; 95% CI, 0.59-1.50), and ertugliflozin/metformin (OR, 0.76; 95% CI, 0.38-1.54).

There were no differences with respect to hip or lumbar spine fractures, or other fractures. The researchers found no differences in bone mineral density or bone turnover markers.

The meta-analysis is limited by the relatively short average follow-up in the included studies, which was 61 weeks. Bone damage may occur over longer time periods. Bone fractures were also not a prespecified adverse event in most included studies.

The studies also did not provide detailed information on the types of fractures experienced, such as whether they were result of a fall, or the location of the fracture, or bone health parameters. Although the results support a belief that SGLT-2 inhibitors do not adversely affect bone health, “given limited information on bone health outcomes, further work is needed to validate this conclusion,” the authors wrote.

The authors did not disclose any funding and had no relevant conflicts of interest.

SOURCE: B-B Qian et al. Osteoporosis Int. 2020 Aug 11. doi: 10.1007/s00198-020-05590-y.

The combination of sodium-glucose transporter-2 (SGLT-2) inhibitors and metformin is not associated with an increase in fracture risk among patients with type 2 diabetes (T2D), according to a new meta-analysis of 25 randomized, controlled trials.

Researchers at The Second Clinical College of Dalian Medical University in Jiangsu, China, compared fracture risk associated with the metformin/SLGT2 combination to metformin alone as well as other T2D therapeutics, and found no differences in risk. The study was published online Aug. 11 in Osteoporosis International.

T2D is associated with an increased risk of fracture, though causative mechanisms remain uncertain. Some lines of evidence suggest multiple factors may contribute to fractures, including hyperglycemia, oxidative stress, toxic effects of advanced glycosylation end-products, altered insulin levels, and treatment-induced hypoglycemia, as well as an association between T2D and increased risk of falls.

Antidiabetes drugs can have positive or negative effects on bone. thiazolidinediones, insulin, and sulfonylureas may increase risk of fractures, while dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-2 (GLP-2) receptor agonists may be protective. Metformin may also reduce fracture risk.

SGLT-2 inhibitors interrupt glucose reabsorption in the kidney, leading to improved glycemic control. Other benefits include improved renal and cardiovascular outcomes, weight loss, and reduced blood pressure, liver fat, and serum uric acid levels.

These properties have made SGLT-2 inhibitors combined with metformin an important therapy for patients at high risk of atherosclerotic disease, or who have heart failure or chronic kidney disease.

But SGLT-2 inhibition increases osmotic diuresis, and this could alter the mineral balance within bone. Some studies also showed that SGLT-2 inhibitors led to changes in bone turnover markers, bone mineral density, and bone microarchitecture. Observational studies of the SGLT-2 inhibitor canagliflozin found associations with a higher rate of fracture risk in patients taking the drug.

Such studies carry the risk of confounding factors, so the researchers took advantage of the fact that many recent clinical trials have examined the impact of SGLT-2 inhibitors on T2D. They pooled data from 25 clinical trials with a total of 19,500 participants, 9,662 of whom received SGLT-2 inhibitors plus metformin; 9,838 received other active comparators.

The fracture rate was 0.91% in the SGLT-2 inhibitors/metformin group, and 0.80% among controls (odds ratio, 0.97; 95% CI, 0.71-1.32), with no heterogeneity. Metformin alone was not associated with a change in fracture rate (OR, 0.95; 95% CI, 0.44-2.08), nor were other forms of diabetes control (OR, 0.95; 95% CI, 0.69-1.31).

There were some differences in fracture risk among SGLT-2 inhibitors when studied individually, though none differed significantly from controls. The highest risk was associated with the canagliflozin/metformin (OR, 2.19; 95% CI, 0.66-7.27), followed by dapagliflozin/metformin (OR, 0.91; 95% CI, 0.50-1.64), empagliflozin/metformin (OR, 0.94; 95% CI, 0.59-1.50), and ertugliflozin/metformin (OR, 0.76; 95% CI, 0.38-1.54).

There were no differences with respect to hip or lumbar spine fractures, or other fractures. The researchers found no differences in bone mineral density or bone turnover markers.

The meta-analysis is limited by the relatively short average follow-up in the included studies, which was 61 weeks. Bone damage may occur over longer time periods. Bone fractures were also not a prespecified adverse event in most included studies.

The studies also did not provide detailed information on the types of fractures experienced, such as whether they were result of a fall, or the location of the fracture, or bone health parameters. Although the results support a belief that SGLT-2 inhibitors do not adversely affect bone health, “given limited information on bone health outcomes, further work is needed to validate this conclusion,” the authors wrote.

The authors did not disclose any funding and had no relevant conflicts of interest.

SOURCE: B-B Qian et al. Osteoporosis Int. 2020 Aug 11. doi: 10.1007/s00198-020-05590-y.

The combination of sodium-glucose transporter-2 (SGLT-2) inhibitors and metformin is not associated with an increase in fracture risk among patients with type 2 diabetes (T2D), according to a new meta-analysis of 25 randomized, controlled trials.

Researchers at The Second Clinical College of Dalian Medical University in Jiangsu, China, compared fracture risk associated with the metformin/SLGT2 combination to metformin alone as well as other T2D therapeutics, and found no differences in risk. The study was published online Aug. 11 in Osteoporosis International.

T2D is associated with an increased risk of fracture, though causative mechanisms remain uncertain. Some lines of evidence suggest multiple factors may contribute to fractures, including hyperglycemia, oxidative stress, toxic effects of advanced glycosylation end-products, altered insulin levels, and treatment-induced hypoglycemia, as well as an association between T2D and increased risk of falls.

Antidiabetes drugs can have positive or negative effects on bone. thiazolidinediones, insulin, and sulfonylureas may increase risk of fractures, while dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-2 (GLP-2) receptor agonists may be protective. Metformin may also reduce fracture risk.

SGLT-2 inhibitors interrupt glucose reabsorption in the kidney, leading to improved glycemic control. Other benefits include improved renal and cardiovascular outcomes, weight loss, and reduced blood pressure, liver fat, and serum uric acid levels.

These properties have made SGLT-2 inhibitors combined with metformin an important therapy for patients at high risk of atherosclerotic disease, or who have heart failure or chronic kidney disease.

But SGLT-2 inhibition increases osmotic diuresis, and this could alter the mineral balance within bone. Some studies also showed that SGLT-2 inhibitors led to changes in bone turnover markers, bone mineral density, and bone microarchitecture. Observational studies of the SGLT-2 inhibitor canagliflozin found associations with a higher rate of fracture risk in patients taking the drug.

Such studies carry the risk of confounding factors, so the researchers took advantage of the fact that many recent clinical trials have examined the impact of SGLT-2 inhibitors on T2D. They pooled data from 25 clinical trials with a total of 19,500 participants, 9,662 of whom received SGLT-2 inhibitors plus metformin; 9,838 received other active comparators.

The fracture rate was 0.91% in the SGLT-2 inhibitors/metformin group, and 0.80% among controls (odds ratio, 0.97; 95% CI, 0.71-1.32), with no heterogeneity. Metformin alone was not associated with a change in fracture rate (OR, 0.95; 95% CI, 0.44-2.08), nor were other forms of diabetes control (OR, 0.95; 95% CI, 0.69-1.31).

There were some differences in fracture risk among SGLT-2 inhibitors when studied individually, though none differed significantly from controls. The highest risk was associated with the canagliflozin/metformin (OR, 2.19; 95% CI, 0.66-7.27), followed by dapagliflozin/metformin (OR, 0.91; 95% CI, 0.50-1.64), empagliflozin/metformin (OR, 0.94; 95% CI, 0.59-1.50), and ertugliflozin/metformin (OR, 0.76; 95% CI, 0.38-1.54).

There were no differences with respect to hip or lumbar spine fractures, or other fractures. The researchers found no differences in bone mineral density or bone turnover markers.

The meta-analysis is limited by the relatively short average follow-up in the included studies, which was 61 weeks. Bone damage may occur over longer time periods. Bone fractures were also not a prespecified adverse event in most included studies.

The studies also did not provide detailed information on the types of fractures experienced, such as whether they were result of a fall, or the location of the fracture, or bone health parameters. Although the results support a belief that SGLT-2 inhibitors do not adversely affect bone health, “given limited information on bone health outcomes, further work is needed to validate this conclusion,” the authors wrote.

The authors did not disclose any funding and had no relevant conflicts of interest.

SOURCE: B-B Qian et al. Osteoporosis Int. 2020 Aug 11. doi: 10.1007/s00198-020-05590-y.

Repeat bone mineral density testing did not improve fracture-risk prediction in a large prospective cohort of postmenopausal women beyond baseline BMD measurement alone, according to new 12-year follow-up data.

Thinkstock

On the basis of the findings, published online in JAMA Internal Medicine, the authors recommend against routine repeat testing in postmenopausal women. Other experts, however, caution that the results may not be so broadly generalizable.

For the investigation, Carolyn J. Crandall, MD, of the division of general internal medicine and health services research at the University of California, Los Angeles, and colleagues analyzed data from 7,419 women enrolled in the prospective Women’s Health Initiative study and who underwent baseline and repeat dual-energy x-ray absorptiometry (DXA) between 1993 and 2010. The researchers excluded patients who reported using bisphosphonates, calcitonin, or selective estrogen-receptor modulators, those with a history of major osteoporotic fracture, or those who lacked follow-up visits. The mean body mass index (BMI) of the study population was 28.7 kg/m², and the mean age was 66.1 years.

The mean follow-up after the repeat BMD test was 9.0 years, during which period 732 (9.9%) of the women experienced a major osteoporotic fracture, and 139 (1.9%) experienced hip fractures.

To determine whether repeat testing improved fracture risk discrimination, the researchers calculated area under the receiver operating characteristic curve (AUROC) for baseline BMD, absolute change in BMD, and the combination of baseline BMD and change in BMD.

With respect to any major osteoporotic fracture risk, the AUROC values for total hip BMD at baseline, change in total hip BMD at 3 years, and the combination of the two, respectively, were 0.61 (95% confidence interval, 0.59-0.63), 0.53 (95% CI, 0.51-0.55), and 0.61 (95% CI, 0.59-0.63). For hip fracture risk, the respective AUROC values were 0.71 (95% CI, 0.67-0.75), 0.61 (95% CI, 0.56-0.65), and 0.73 (95% CI, 0.69-0.77), the authors reported.

Similar results were observed for femoral neck and lumbar spine BMD measurements. The associations between BMD changes and fracture risk were consistent across age, race, ethnicity, BMI, and baseline BMD T-score subgroups.

Although baseline BMD and change in BMD were independently associated with incident fracture, the association was stronger for lower baseline BMD than the 3-year absolute change in BMD, the authors stated.

The findings, which are consistent with those of previous investigations that involved older adults, are notable because of the age range of the population, according to the authors. “To our knowledge, this is the first prospective study that addressed this issue in a study cohort that included younger postmenopausal U.S. women,” they wrote. “Forty-four percent of our study population was younger than 65 years.”

The authors wrote that, given the lack of benefit associated with repeat BMD testing, such tests should no longer be routinely performed. “Our findings further suggest that resources should be devoted to increasing the underuse of baseline BMD testing among women aged [between] 65 and 85 years, one-quarter of whom do not receive an initial BMD test.”

Loyola University

However, some experts are not comfortable with the broad recommendation to skip repeat testing in the general population. “This is a great study, and it gives important information. However, we know, even in the real world, that patients can lose BMD in this time frame and not really fracture. This does not mean that they will not fracture further down the road,” said Pauline Camacho, MD, director of Loyola University Medical Center’s Osteoporosis and Metabolic Bone Disease Center in Chicago,. “The value of doing BMD goes beyond predicting fracture risk. It also helps assess patient compliance and detect the presence of uncorrected secondary causes of osteoporosis that are limiting the response to therapy, including failure to absorb oral bisphosphonates, vitamin D deficiency, or hyperparathyroidism.”

In addition, patients for whom treatment is initiated would want to know whether it’s working. “Seeing the BMD response to therapy is helpful to both clinicians and patients,” Dr. Camacho said in an interview.

Another concern is the study population. “The study was designed to assess the clinical utility of repeating a screening BMD test in a population of low-risk women -- older postmenopausal women with remarkably good BMD on initial testing,” according to E. Michael Lewiecki, MD, vice president of the National Osteoporosis Foundation and director of the New Mexico Clinical Research and Osteoporosis Center in Albuquerque. “Not surprisingly, with what we know about the expected age-related rate of bone loss, there was only a modest decrease in BMD and little clinical utility in repeating DXA in 3 years. However, repeat testing is an important component in the care of many patients seen in clinical practice.”

UNM Health Sciences Center

There are numerous situations in clinical practice in which repeat BMD testing can enhance patient care and potentially improve outcomes, Dr. Lewiecki said in an interview. “Repeating BMD 1-2 years after starting osteoporosis therapy is a useful way to assess response and determine whether the patient is on a pathway to achieving an acceptable level of fracture risk with a strategy called treat to target.”

Additionally, patients starting high-dose glucocorticoids who are at high risk for rapid bone loss may benefit from undergoing baseline BMD testing and having a follow-up test 1 year later or even sooner, he said. Further, for early postmenopausal women, the rate of bone loss may be accelerated and may be faster than age-related bone loss later in life. For this reason, “close monitoring of BMD may be used to determine when a treatment threshold has been crossed and pharmacological therapy is indicated.”

The most important message from this study for clinicians and healthcare policymakers is not the relative value of the repeat BMD testing, Dr. Lewiecki stated. Rather, it is the call to action regarding the underuse of BMD testing. “There is a global crisis in the care of osteoporosis that is characterized by underdiagnosis and undertreatment of patients at risk for fracture. Many patients who could benefit from treatment to reduce fracture risk are not receiving it, resulting in disability and deaths from fractures that might have been prevented. We need more bone density testing in appropriately selected patients to identify high-risk patients and intervene to reduce fracture risk,” he said. “DXA is an inexpensive and highly versatile clinical tool with many applications in clinical practice. When used wisely, it can be extraordinarily useful to identify and monitor high-risk patients, with the goal of reducing the burden of osteoporotic fractures.”

The barriers to performing baseline BMD measurement in this population are poorly understood and not well researched, Dr. Crandall said in an interview. “I expect that they relate to the multiple competing demands on primary care physicians, who are, for example, trying to juggle hypertension, a sprained ankle, diabetes, and complex social situations simultaneously with identifying appropriate candidates for osteoporosis screening and considering numerous other screening guidelines.”

The Women’s Health Initiative is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The study authors reported relationships with multiple companies, including Amgen, Pfizer, Bayer, Mithra, Norton Rose Fulbright, TherapeuticsMD, AbbVie, Radius, and Allergan. Dr. Camacho reported relationships with Amgen and Shire. Dr. Lewiecki reported relationships with Amgen, Radius Health, Alexion, Samsung Bioepis, Sandoz, Mereo, and Bindex.

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

Repeat bone mineral density testing did not improve fracture-risk prediction in a large prospective cohort of postmenopausal women beyond baseline BMD measurement alone, according to new 12-year follow-up data.

Thinkstock

On the basis of the findings, published online in JAMA Internal Medicine, the authors recommend against routine repeat testing in postmenopausal women. Other experts, however, caution that the results may not be so broadly generalizable.

For the investigation, Carolyn J. Crandall, MD, of the division of general internal medicine and health services research at the University of California, Los Angeles, and colleagues analyzed data from 7,419 women enrolled in the prospective Women’s Health Initiative study and who underwent baseline and repeat dual-energy x-ray absorptiometry (DXA) between 1993 and 2010. The researchers excluded patients who reported using bisphosphonates, calcitonin, or selective estrogen-receptor modulators, those with a history of major osteoporotic fracture, or those who lacked follow-up visits. The mean body mass index (BMI) of the study population was 28.7 kg/m², and the mean age was 66.1 years.

The mean follow-up after the repeat BMD test was 9.0 years, during which period 732 (9.9%) of the women experienced a major osteoporotic fracture, and 139 (1.9%) experienced hip fractures.

To determine whether repeat testing improved fracture risk discrimination, the researchers calculated area under the receiver operating characteristic curve (AUROC) for baseline BMD, absolute change in BMD, and the combination of baseline BMD and change in BMD.

With respect to any major osteoporotic fracture risk, the AUROC values for total hip BMD at baseline, change in total hip BMD at 3 years, and the combination of the two, respectively, were 0.61 (95% confidence interval, 0.59-0.63), 0.53 (95% CI, 0.51-0.55), and 0.61 (95% CI, 0.59-0.63). For hip fracture risk, the respective AUROC values were 0.71 (95% CI, 0.67-0.75), 0.61 (95% CI, 0.56-0.65), and 0.73 (95% CI, 0.69-0.77), the authors reported.

Similar results were observed for femoral neck and lumbar spine BMD measurements. The associations between BMD changes and fracture risk were consistent across age, race, ethnicity, BMI, and baseline BMD T-score subgroups.

Although baseline BMD and change in BMD were independently associated with incident fracture, the association was stronger for lower baseline BMD than the 3-year absolute change in BMD, the authors stated.

The findings, which are consistent with those of previous investigations that involved older adults, are notable because of the age range of the population, according to the authors. “To our knowledge, this is the first prospective study that addressed this issue in a study cohort that included younger postmenopausal U.S. women,” they wrote. “Forty-four percent of our study population was younger than 65 years.”

The authors wrote that, given the lack of benefit associated with repeat BMD testing, such tests should no longer be routinely performed. “Our findings further suggest that resources should be devoted to increasing the underuse of baseline BMD testing among women aged [between] 65 and 85 years, one-quarter of whom do not receive an initial BMD test.”

Loyola University

However, some experts are not comfortable with the broad recommendation to skip repeat testing in the general population. “This is a great study, and it gives important information. However, we know, even in the real world, that patients can lose BMD in this time frame and not really fracture. This does not mean that they will not fracture further down the road,” said Pauline Camacho, MD, director of Loyola University Medical Center’s Osteoporosis and Metabolic Bone Disease Center in Chicago,. “The value of doing BMD goes beyond predicting fracture risk. It also helps assess patient compliance and detect the presence of uncorrected secondary causes of osteoporosis that are limiting the response to therapy, including failure to absorb oral bisphosphonates, vitamin D deficiency, or hyperparathyroidism.”

In addition, patients for whom treatment is initiated would want to know whether it’s working. “Seeing the BMD response to therapy is helpful to both clinicians and patients,” Dr. Camacho said in an interview.

Another concern is the study population. “The study was designed to assess the clinical utility of repeating a screening BMD test in a population of low-risk women -- older postmenopausal women with remarkably good BMD on initial testing,” according to E. Michael Lewiecki, MD, vice president of the National Osteoporosis Foundation and director of the New Mexico Clinical Research and Osteoporosis Center in Albuquerque. “Not surprisingly, with what we know about the expected age-related rate of bone loss, there was only a modest decrease in BMD and little clinical utility in repeating DXA in 3 years. However, repeat testing is an important component in the care of many patients seen in clinical practice.”

UNM Health Sciences Center

There are numerous situations in clinical practice in which repeat BMD testing can enhance patient care and potentially improve outcomes, Dr. Lewiecki said in an interview. “Repeating BMD 1-2 years after starting osteoporosis therapy is a useful way to assess response and determine whether the patient is on a pathway to achieving an acceptable level of fracture risk with a strategy called treat to target.”

Additionally, patients starting high-dose glucocorticoids who are at high risk for rapid bone loss may benefit from undergoing baseline BMD testing and having a follow-up test 1 year later or even sooner, he said. Further, for early postmenopausal women, the rate of bone loss may be accelerated and may be faster than age-related bone loss later in life. For this reason, “close monitoring of BMD may be used to determine when a treatment threshold has been crossed and pharmacological therapy is indicated.”

The most important message from this study for clinicians and healthcare policymakers is not the relative value of the repeat BMD testing, Dr. Lewiecki stated. Rather, it is the call to action regarding the underuse of BMD testing. “There is a global crisis in the care of osteoporosis that is characterized by underdiagnosis and undertreatment of patients at risk for fracture. Many patients who could benefit from treatment to reduce fracture risk are not receiving it, resulting in disability and deaths from fractures that might have been prevented. We need more bone density testing in appropriately selected patients to identify high-risk patients and intervene to reduce fracture risk,” he said. “DXA is an inexpensive and highly versatile clinical tool with many applications in clinical practice. When used wisely, it can be extraordinarily useful to identify and monitor high-risk patients, with the goal of reducing the burden of osteoporotic fractures.”

The barriers to performing baseline BMD measurement in this population are poorly understood and not well researched, Dr. Crandall said in an interview. “I expect that they relate to the multiple competing demands on primary care physicians, who are, for example, trying to juggle hypertension, a sprained ankle, diabetes, and complex social situations simultaneously with identifying appropriate candidates for osteoporosis screening and considering numerous other screening guidelines.”

The Women’s Health Initiative is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The study authors reported relationships with multiple companies, including Amgen, Pfizer, Bayer, Mithra, Norton Rose Fulbright, TherapeuticsMD, AbbVie, Radius, and Allergan. Dr. Camacho reported relationships with Amgen and Shire. Dr. Lewiecki reported relationships with Amgen, Radius Health, Alexion, Samsung Bioepis, Sandoz, Mereo, and Bindex.

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

Repeat bone mineral density testing did not improve fracture-risk prediction in a large prospective cohort of postmenopausal women beyond baseline BMD measurement alone, according to new 12-year follow-up data.

Thinkstock

On the basis of the findings, published online in JAMA Internal Medicine, the authors recommend against routine repeat testing in postmenopausal women. Other experts, however, caution that the results may not be so broadly generalizable.

For the investigation, Carolyn J. Crandall, MD, of the division of general internal medicine and health services research at the University of California, Los Angeles, and colleagues analyzed data from 7,419 women enrolled in the prospective Women’s Health Initiative study and who underwent baseline and repeat dual-energy x-ray absorptiometry (DXA) between 1993 and 2010. The researchers excluded patients who reported using bisphosphonates, calcitonin, or selective estrogen-receptor modulators, those with a history of major osteoporotic fracture, or those who lacked follow-up visits. The mean body mass index (BMI) of the study population was 28.7 kg/m², and the mean age was 66.1 years.

The mean follow-up after the repeat BMD test was 9.0 years, during which period 732 (9.9%) of the women experienced a major osteoporotic fracture, and 139 (1.9%) experienced hip fractures.

To determine whether repeat testing improved fracture risk discrimination, the researchers calculated area under the receiver operating characteristic curve (AUROC) for baseline BMD, absolute change in BMD, and the combination of baseline BMD and change in BMD.

With respect to any major osteoporotic fracture risk, the AUROC values for total hip BMD at baseline, change in total hip BMD at 3 years, and the combination of the two, respectively, were 0.61 (95% confidence interval, 0.59-0.63), 0.53 (95% CI, 0.51-0.55), and 0.61 (95% CI, 0.59-0.63). For hip fracture risk, the respective AUROC values were 0.71 (95% CI, 0.67-0.75), 0.61 (95% CI, 0.56-0.65), and 0.73 (95% CI, 0.69-0.77), the authors reported.

Similar results were observed for femoral neck and lumbar spine BMD measurements. The associations between BMD changes and fracture risk were consistent across age, race, ethnicity, BMI, and baseline BMD T-score subgroups.

Although baseline BMD and change in BMD were independently associated with incident fracture, the association was stronger for lower baseline BMD than the 3-year absolute change in BMD, the authors stated.

The findings, which are consistent with those of previous investigations that involved older adults, are notable because of the age range of the population, according to the authors. “To our knowledge, this is the first prospective study that addressed this issue in a study cohort that included younger postmenopausal U.S. women,” they wrote. “Forty-four percent of our study population was younger than 65 years.”

The authors wrote that, given the lack of benefit associated with repeat BMD testing, such tests should no longer be routinely performed. “Our findings further suggest that resources should be devoted to increasing the underuse of baseline BMD testing among women aged [between] 65 and 85 years, one-quarter of whom do not receive an initial BMD test.”

Loyola University

However, some experts are not comfortable with the broad recommendation to skip repeat testing in the general population. “This is a great study, and it gives important information. However, we know, even in the real world, that patients can lose BMD in this time frame and not really fracture. This does not mean that they will not fracture further down the road,” said Pauline Camacho, MD, director of Loyola University Medical Center’s Osteoporosis and Metabolic Bone Disease Center in Chicago,. “The value of doing BMD goes beyond predicting fracture risk. It also helps assess patient compliance and detect the presence of uncorrected secondary causes of osteoporosis that are limiting the response to therapy, including failure to absorb oral bisphosphonates, vitamin D deficiency, or hyperparathyroidism.”

In addition, patients for whom treatment is initiated would want to know whether it’s working. “Seeing the BMD response to therapy is helpful to both clinicians and patients,” Dr. Camacho said in an interview.

Another concern is the study population. “The study was designed to assess the clinical utility of repeating a screening BMD test in a population of low-risk women -- older postmenopausal women with remarkably good BMD on initial testing,” according to E. Michael Lewiecki, MD, vice president of the National Osteoporosis Foundation and director of the New Mexico Clinical Research and Osteoporosis Center in Albuquerque. “Not surprisingly, with what we know about the expected age-related rate of bone loss, there was only a modest decrease in BMD and little clinical utility in repeating DXA in 3 years. However, repeat testing is an important component in the care of many patients seen in clinical practice.”

UNM Health Sciences Center

There are numerous situations in clinical practice in which repeat BMD testing can enhance patient care and potentially improve outcomes, Dr. Lewiecki said in an interview. “Repeating BMD 1-2 years after starting osteoporosis therapy is a useful way to assess response and determine whether the patient is on a pathway to achieving an acceptable level of fracture risk with a strategy called treat to target.”

Additionally, patients starting high-dose glucocorticoids who are at high risk for rapid bone loss may benefit from undergoing baseline BMD testing and having a follow-up test 1 year later or even sooner, he said. Further, for early postmenopausal women, the rate of bone loss may be accelerated and may be faster than age-related bone loss later in life. For this reason, “close monitoring of BMD may be used to determine when a treatment threshold has been crossed and pharmacological therapy is indicated.”

The most important message from this study for clinicians and healthcare policymakers is not the relative value of the repeat BMD testing, Dr. Lewiecki stated. Rather, it is the call to action regarding the underuse of BMD testing. “There is a global crisis in the care of osteoporosis that is characterized by underdiagnosis and undertreatment of patients at risk for fracture. Many patients who could benefit from treatment to reduce fracture risk are not receiving it, resulting in disability and deaths from fractures that might have been prevented. We need more bone density testing in appropriately selected patients to identify high-risk patients and intervene to reduce fracture risk,” he said. “DXA is an inexpensive and highly versatile clinical tool with many applications in clinical practice. When used wisely, it can be extraordinarily useful to identify and monitor high-risk patients, with the goal of reducing the burden of osteoporotic fractures.”

The barriers to performing baseline BMD measurement in this population are poorly understood and not well researched, Dr. Crandall said in an interview. “I expect that they relate to the multiple competing demands on primary care physicians, who are, for example, trying to juggle hypertension, a sprained ankle, diabetes, and complex social situations simultaneously with identifying appropriate candidates for osteoporosis screening and considering numerous other screening guidelines.”

The Women’s Health Initiative is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The study authors reported relationships with multiple companies, including Amgen, Pfizer, Bayer, Mithra, Norton Rose Fulbright, TherapeuticsMD, AbbVie, Radius, and Allergan. Dr. Camacho reported relationships with Amgen and Shire. Dr. Lewiecki reported relationships with Amgen, Radius Health, Alexion, Samsung Bioepis, Sandoz, Mereo, and Bindex.

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

Low plasma vitamin D levels emerged as an independent risk factor for COVID-19 infection and hospitalization in a large, population-based study.

Participants positive for COVID-19 were 50% more likely to have low vs normal 25(OH)D levels in a multivariate analysis that controlled for other confounders, for example.

The take home message for physicians is to “test patients’ vitamin D levels and keep them optimal for the overall health – as well as for a better immunoresponse to COVID-19,” senior author Milana Frenkel-Morgenstern, PhD, head of the Cancer Genomics and BioComputing of Complex Diseases Lab at Bar-Ilan University in Ramat Gan, Israel, said in an interview.

The study was published online July 23 in The FEBS Journal.

Previous and ongoing studies are evaluating a potential role for vitamin D to prevent or minimize the severity of SARS-CoV-2 infection, building on years of research addressing vitamin D for other viral respiratory infections. The evidence to date regarding COVID-19, primarily observational studies, has yielded mixed results.

Multiple experts weighed in on the controversy in a previous report. Many point out the limitations of observational data, particularly when it comes to ruling out other factors that could affect the severity of COVID-19 infection. In addition, in a video report, JoAnn E. Manson, MD, DrPH, of Harvard Medical School in Boston, cited an observational study from three South Asian hospitals that found more severe COVID-19 patients had lower vitamin D levels, as well as other “compelling evidence” suggesting an association.

Dr. Frenkel-Morgenstern and colleagues studied data for 7,807 people, of whom 10.1% were COVID-19 positive. They assessed electronic health records for demographics, potential confounders, and outcomes between February 1 and April 30.

Participants positive for COVID-19 tended to be younger and were more likely to be men and live in a lower socioeconomic area, compared with the participants who were negative for COVID-19, in a univariate analysis.

Key findings

A higher proportion of COVID-19–positive patients had low plasma 25(OH)D concentrations, about 90% versus 85% of participants who were negative for COVID-19. The difference was statistically significant (P < .001). Furthermore, the increased likelihood for low vitamin D levels among those positive for COVID-19 held in a multivariate analysis that controlled for demographics and psychiatric and somatic disorders (adjusted odds ratio, 1.50). The difference remained statistically significant (P < .001).

The study also was noteworthy for what it did not find among participants with COVID-19. For example, the prevalence of dementia, cardiovascular disease, chronic lung disorders, and hypertension were significantly higher among the COVID-19 negative participants.

“Severe social contacts restrictions that were imposed on all the population and were even more emphasized in this highly vulnerable population” could explain these findings, the researchers noted.

“We assume that following the Israeli Ministry of Health instructions, patients with chronic medical conditions significantly reduced their social contacts” and thereby reduced their infection risk.

In contrast to previous reports, obesity was not a significant factor associated with increased likelihood for COVID-19 infection or hospitalization in the current study.

The researchers also linked low plasma 25(OH)D level to an increased likelihood of hospitalization for COVID-19 infection (crude OR, 2.09; P < .05).

After controlling for demographics and chronic disorders, the aOR decreased to 1.95 (P = .061) in a multivariate analysis. The only factor that remained statistically significant for hospitalization was age over 50 years (aOR, 2.71; P < .001).

Implications and future plans

The large number of participants and the “real world,” population-based design are strengths of the study. Considering potential confounders is another strength, the researchers noted. The retrospective database design was a limitation.

Going forward, Dr. Frenkel-Morgenstern and colleagues will “try to decipher the potential role of vitamin D in prevention and/or treatment of COVID-19” through three additional studies, she said. Also, they would like to conduct a meta-analysis to combine data from different countries to further explore the potential role of vitamin D in COVID-19.

“A compelling case”

“This is a strong study – large, adjusted for confounders, consistent with the biology and other clinical studies of vitamin D, infections, and COVID-19,” Wayne Jonas, MD, a practicing family physician and executive director of Samueli Integrative Health Programs, said in an interview.

Because the research was retrospective and observational, a causative link between vitamin D levels and COVID-19 risk cannot be interpreted from the findings. “That would need a prospective, randomized study,” said Dr. Jonas, who was not involved with the current study.

However, “the study makes a compelling case for possibly screening vitamin D levels for judging risk of COVID infection and hospitalization,” Dr. Jonas said, “and the compelling need for a large, randomized vitamin D supplement study to see if it can help prevent infection.”

“Given that vitamin D is largely safe, such a study could be done quickly and on healthy people with minimal risk for harm,” he added.
 

More confounders likely?

“I think the study is of interest,” Naveed Sattar, PhD,  professor of metabolic medicine at the University of Glasgow, who also was not affiliated with the research, said in an interview.

“Whilst the authors adjusted for some confounders, there is a strong potential for residual confounding,” said Dr. Sattar, a coauthor of a UK Biobank study that did not find an association between vitamin D stages and COVID-19 infection in multivariate models.

For example, Dr. Sattar said, “Robust adjustment for social class is important since both Vitamin D levels and COVID-19 severity are both strongly associated with social class.” Further, it remains unknown when and what time of year the vitamin D concentrations were measured in the current study.

“In the end, only a robust randomized trial can tell us whether vitamin D supplementation helps lessen COVID-19 severity,” Dr. Sattar added. “I am not hopeful we will find this is the case – but I am glad some such trials are [ongoing].”

Dr. Frenkel-Morgenstern received a COVID-19 Data Sciences Institute grant to support this work. Dr. Frenkel-Morgenstern, Dr. Jonas, and Dr. Sattar have disclosed no relevant financial relationships.
 

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

Low plasma vitamin D levels emerged as an independent risk factor for COVID-19 infection and hospitalization in a large, population-based study.

Participants positive for COVID-19 were 50% more likely to have low vs normal 25(OH)D levels in a multivariate analysis that controlled for other confounders, for example.

The take home message for physicians is to “test patients’ vitamin D levels and keep them optimal for the overall health – as well as for a better immunoresponse to COVID-19,” senior author Milana Frenkel-Morgenstern, PhD, head of the Cancer Genomics and BioComputing of Complex Diseases Lab at Bar-Ilan University in Ramat Gan, Israel, said in an interview.

The study was published online July 23 in The FEBS Journal.

Previous and ongoing studies are evaluating a potential role for vitamin D to prevent or minimize the severity of SARS-CoV-2 infection, building on years of research addressing vitamin D for other viral respiratory infections. The evidence to date regarding COVID-19, primarily observational studies, has yielded mixed results.

Multiple experts weighed in on the controversy in a previous report. Many point out the limitations of observational data, particularly when it comes to ruling out other factors that could affect the severity of COVID-19 infection. In addition, in a video report, JoAnn E. Manson, MD, DrPH, of Harvard Medical School in Boston, cited an observational study from three South Asian hospitals that found more severe COVID-19 patients had lower vitamin D levels, as well as other “compelling evidence” suggesting an association.

Dr. Frenkel-Morgenstern and colleagues studied data for 7,807 people, of whom 10.1% were COVID-19 positive. They assessed electronic health records for demographics, potential confounders, and outcomes between February 1 and April 30.

Participants positive for COVID-19 tended to be younger and were more likely to be men and live in a lower socioeconomic area, compared with the participants who were negative for COVID-19, in a univariate analysis.

Key findings

A higher proportion of COVID-19–positive patients had low plasma 25(OH)D concentrations, about 90% versus 85% of participants who were negative for COVID-19. The difference was statistically significant (P < .001). Furthermore, the increased likelihood for low vitamin D levels among those positive for COVID-19 held in a multivariate analysis that controlled for demographics and psychiatric and somatic disorders (adjusted odds ratio, 1.50). The difference remained statistically significant (P < .001).

The study also was noteworthy for what it did not find among participants with COVID-19. For example, the prevalence of dementia, cardiovascular disease, chronic lung disorders, and hypertension were significantly higher among the COVID-19 negative participants.

“Severe social contacts restrictions that were imposed on all the population and were even more emphasized in this highly vulnerable population” could explain these findings, the researchers noted.

“We assume that following the Israeli Ministry of Health instructions, patients with chronic medical conditions significantly reduced their social contacts” and thereby reduced their infection risk.

In contrast to previous reports, obesity was not a significant factor associated with increased likelihood for COVID-19 infection or hospitalization in the current study.

The researchers also linked low plasma 25(OH)D level to an increased likelihood of hospitalization for COVID-19 infection (crude OR, 2.09; P < .05).

After controlling for demographics and chronic disorders, the aOR decreased to 1.95 (P = .061) in a multivariate analysis. The only factor that remained statistically significant for hospitalization was age over 50 years (aOR, 2.71; P < .001).

Implications and future plans

The large number of participants and the “real world,” population-based design are strengths of the study. Considering potential confounders is another strength, the researchers noted. The retrospective database design was a limitation.

Going forward, Dr. Frenkel-Morgenstern and colleagues will “try to decipher the potential role of vitamin D in prevention and/or treatment of COVID-19” through three additional studies, she said. Also, they would like to conduct a meta-analysis to combine data from different countries to further explore the potential role of vitamin D in COVID-19.

“A compelling case”

“This is a strong study – large, adjusted for confounders, consistent with the biology and other clinical studies of vitamin D, infections, and COVID-19,” Wayne Jonas, MD, a practicing family physician and executive director of Samueli Integrative Health Programs, said in an interview.

Because the research was retrospective and observational, a causative link between vitamin D levels and COVID-19 risk cannot be interpreted from the findings. “That would need a prospective, randomized study,” said Dr. Jonas, who was not involved with the current study.

However, “the study makes a compelling case for possibly screening vitamin D levels for judging risk of COVID infection and hospitalization,” Dr. Jonas said, “and the compelling need for a large, randomized vitamin D supplement study to see if it can help prevent infection.”

“Given that vitamin D is largely safe, such a study could be done quickly and on healthy people with minimal risk for harm,” he added.
 

More confounders likely?

“I think the study is of interest,” Naveed Sattar, PhD,  professor of metabolic medicine at the University of Glasgow, who also was not affiliated with the research, said in an interview.

“Whilst the authors adjusted for some confounders, there is a strong potential for residual confounding,” said Dr. Sattar, a coauthor of a UK Biobank study that did not find an association between vitamin D stages and COVID-19 infection in multivariate models.

For example, Dr. Sattar said, “Robust adjustment for social class is important since both Vitamin D levels and COVID-19 severity are both strongly associated with social class.” Further, it remains unknown when and what time of year the vitamin D concentrations were measured in the current study.

“In the end, only a robust randomized trial can tell us whether vitamin D supplementation helps lessen COVID-19 severity,” Dr. Sattar added. “I am not hopeful we will find this is the case – but I am glad some such trials are [ongoing].”

Dr. Frenkel-Morgenstern received a COVID-19 Data Sciences Institute grant to support this work. Dr. Frenkel-Morgenstern, Dr. Jonas, and Dr. Sattar have disclosed no relevant financial relationships.
 

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

Low plasma vitamin D levels emerged as an independent risk factor for COVID-19 infection and hospitalization in a large, population-based study.

Participants positive for COVID-19 were 50% more likely to have low vs normal 25(OH)D levels in a multivariate analysis that controlled for other confounders, for example.

The take home message for physicians is to “test patients’ vitamin D levels and keep them optimal for the overall health – as well as for a better immunoresponse to COVID-19,” senior author Milana Frenkel-Morgenstern, PhD, head of the Cancer Genomics and BioComputing of Complex Diseases Lab at Bar-Ilan University in Ramat Gan, Israel, said in an interview.

The study was published online July 23 in The FEBS Journal.

Previous and ongoing studies are evaluating a potential role for vitamin D to prevent or minimize the severity of SARS-CoV-2 infection, building on years of research addressing vitamin D for other viral respiratory infections. The evidence to date regarding COVID-19, primarily observational studies, has yielded mixed results.

Multiple experts weighed in on the controversy in a previous report. Many point out the limitations of observational data, particularly when it comes to ruling out other factors that could affect the severity of COVID-19 infection. In addition, in a video report, JoAnn E. Manson, MD, DrPH, of Harvard Medical School in Boston, cited an observational study from three South Asian hospitals that found more severe COVID-19 patients had lower vitamin D levels, as well as other “compelling evidence” suggesting an association.

Dr. Frenkel-Morgenstern and colleagues studied data for 7,807 people, of whom 10.1% were COVID-19 positive. They assessed electronic health records for demographics, potential confounders, and outcomes between February 1 and April 30.

Participants positive for COVID-19 tended to be younger and were more likely to be men and live in a lower socioeconomic area, compared with the participants who were negative for COVID-19, in a univariate analysis.

Key findings

A higher proportion of COVID-19–positive patients had low plasma 25(OH)D concentrations, about 90% versus 85% of participants who were negative for COVID-19. The difference was statistically significant (P < .001). Furthermore, the increased likelihood for low vitamin D levels among those positive for COVID-19 held in a multivariate analysis that controlled for demographics and psychiatric and somatic disorders (adjusted odds ratio, 1.50). The difference remained statistically significant (P < .001).

The study also was noteworthy for what it did not find among participants with COVID-19. For example, the prevalence of dementia, cardiovascular disease, chronic lung disorders, and hypertension were significantly higher among the COVID-19 negative participants.

“Severe social contacts restrictions that were imposed on all the population and were even more emphasized in this highly vulnerable population” could explain these findings, the researchers noted.

“We assume that following the Israeli Ministry of Health instructions, patients with chronic medical conditions significantly reduced their social contacts” and thereby reduced their infection risk.

In contrast to previous reports, obesity was not a significant factor associated with increased likelihood for COVID-19 infection or hospitalization in the current study.

The researchers also linked low plasma 25(OH)D level to an increased likelihood of hospitalization for COVID-19 infection (crude OR, 2.09; P < .05).

After controlling for demographics and chronic disorders, the aOR decreased to 1.95 (P = .061) in a multivariate analysis. The only factor that remained statistically significant for hospitalization was age over 50 years (aOR, 2.71; P < .001).

Implications and future plans

The large number of participants and the “real world,” population-based design are strengths of the study. Considering potential confounders is another strength, the researchers noted. The retrospective database design was a limitation.

Going forward, Dr. Frenkel-Morgenstern and colleagues will “try to decipher the potential role of vitamin D in prevention and/or treatment of COVID-19” through three additional studies, she said. Also, they would like to conduct a meta-analysis to combine data from different countries to further explore the potential role of vitamin D in COVID-19.

“A compelling case”

“This is a strong study – large, adjusted for confounders, consistent with the biology and other clinical studies of vitamin D, infections, and COVID-19,” Wayne Jonas, MD, a practicing family physician and executive director of Samueli Integrative Health Programs, said in an interview.

Because the research was retrospective and observational, a causative link between vitamin D levels and COVID-19 risk cannot be interpreted from the findings. “That would need a prospective, randomized study,” said Dr. Jonas, who was not involved with the current study.

However, “the study makes a compelling case for possibly screening vitamin D levels for judging risk of COVID infection and hospitalization,” Dr. Jonas said, “and the compelling need for a large, randomized vitamin D supplement study to see if it can help prevent infection.”

“Given that vitamin D is largely safe, such a study could be done quickly and on healthy people with minimal risk for harm,” he added.
 

More confounders likely?

“I think the study is of interest,” Naveed Sattar, PhD,  professor of metabolic medicine at the University of Glasgow, who also was not affiliated with the research, said in an interview.

“Whilst the authors adjusted for some confounders, there is a strong potential for residual confounding,” said Dr. Sattar, a coauthor of a UK Biobank study that did not find an association between vitamin D stages and COVID-19 infection in multivariate models.

For example, Dr. Sattar said, “Robust adjustment for social class is important since both Vitamin D levels and COVID-19 severity are both strongly associated with social class.” Further, it remains unknown when and what time of year the vitamin D concentrations were measured in the current study.

“In the end, only a robust randomized trial can tell us whether vitamin D supplementation helps lessen COVID-19 severity,” Dr. Sattar added. “I am not hopeful we will find this is the case – but I am glad some such trials are [ongoing].”

Dr. Frenkel-Morgenstern received a COVID-19 Data Sciences Institute grant to support this work. Dr. Frenkel-Morgenstern, Dr. Jonas, and Dr. Sattar have disclosed no relevant financial relationships.
 

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

Delaying doses of denosumab after the first injection dramatically boosts the risk that patients with osteoporosis will suffer vertebral fractures, a new study confirms. Physicians say they are especially concerned about the risk facing patients who are delaying the treatment during the coronavirus pandemic.

doble-d/Getty Images

The recommended doses of denosumab are at 6-month intervals. Patients who delayed a dose by more than 16 weeks were nearly four times more likely to suffer vertebral fractures, compared with those who received on-time injections, according to the study, which was published in Annals of Internal Medicine.

“Because patients who used denosumab were at high risk for vertebral fracture, strategies to improve timely administration of denosumab in routine clinical settings are needed,” wrote the study authors, led by Houchen Lyu, MD, PhD, of National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation at General Hospital of Chinese PLA in Beijing.

Denosumab, a human monoclonal antibody, is used to reduce bone loss in osteoporosis. The manufacturer of Prolia, a brand of the drug, recommends it be given every 6 months, but the study reports that it’s common for injections to be delayed.

Researchers have linked cessation of denosumab to higher risk of fractures, and Dr. Lyu led a study published earlier this year that linked less-frequent doses to less bone mineral density improvement. “However,” the authors of the new study wrote, “whether delaying subsequent injections beyond the recommended 6-month interval is associated with fractures is unknown.”

For their new study, researchers retrospectively analyzed data from 2,594 patients in the U.K. 45 years or older (mean age, 76; 94% female; 53% with a history of major osteoporotic fracture) who began taking denosumab between 2010 and 2019. They used a design that aimed to emulate a clinical trial, comparing three dosing intervals: “on time” (within 4 weeks of the recommended 6-month interval), “short delay” (within 4-16 weeks) and “long delay” (16 weeks to 6 months).

The study found that the risk of composite fracture over 6 months out of 1,000 was 27.3 for on-time dosing, 32.2 for short-delay dosing, and 42.4 for long-delay dosing. The hazard ratio for long-delay versus on-time was 1.44 (95% confidence interval, 0.96-2.17; P = .093).

Vertebral fractures were less likely, but delays boosted the risk significantly: Over 6 months, it grew from 2.2 in 1,000 (on time) to 3.6 in 1,000 (short delay) and 10.1 in 1,000 (long delay). The HR for long delay versus on time was 3.91 (95% CI, 1.62-9.45; P = .005).

“This study had limited statistical power for composite fracture and several secondary end points ... except for vertebral fracture. Thus, evidence was insufficient to conclude that fracture risk was increased at other anatomical sites.”

In an accompanying editorial, two physicians from the University of Minnesota, Minneapolis, noted that the study is “timely and relevant” since the coronavirus pandemic may disrupt dosage schedules more than usual. While the study has limitations, the “findings are consistent with known denosumab pharmacokinetics and prior studies of fracture incidence after denosumab treatment discontinuation, wrote Kristine E. Ensrud, MD, MPH, who is also of Minneapolis VA Health Care System, and John T. Schousboe, MD, PhD, who is also of HealthPartners Institute.

The editorial authors noted that, in light of the pandemic, “some organizations recommend temporary transition to an oral bisphosphonate in patients receiving denosumab treatment for whom continued treatment is not feasible within 7 to 8 months of their most recent injection.”

In an interview, endocrinologist and osteoporosis specialist Ethel Siris, MD, of Columbia University, New York, said many of her patients aren’t coming in for denosumab injections during the pandemic. “It’s hard enough to get people to show up every 6 months to get their shot when things are going nicely,” she said. “We’re talking older women who may be on a lot of other medications. People forget, and it’s difficult for the office to constantly remind some of them to get their shots at an infusion center.”

The lack of symptoms is another challenge to getting patients to return for doses, she said. “In osteoporosis, the only time something hurts is if you break it.”

Since the pandemic began, many patients have been avoiding medical offices because of fear of getting the coronavirus.

The new research is helpful because it shows that patients are “more likely to fracture if they delay,” Dr. Siris noted. The endocrinologist added that she has successfully convinced some patients to give themselves subcutaneous injections in the abdomen at home.

Dr. Siris said she has been able to watch patients do these injections on video to check their technique. Her patients have been impressed by “how easy it is and delighted to have accomplished it,” she said.

The study was funded by the National Institutes of Health China’s National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation. The study authors, commentary authors, and Dr. Siris report no relevant disclosures.
 

SOURCE: Lyu H et al. Ann Intern Med. 2020 Jul 28. doi: 10.7326/M20-0882.

Delaying doses of denosumab after the first injection dramatically boosts the risk that patients with osteoporosis will suffer vertebral fractures, a new study confirms. Physicians say they are especially concerned about the risk facing patients who are delaying the treatment during the coronavirus pandemic.

doble-d/Getty Images

The recommended doses of denosumab are at 6-month intervals. Patients who delayed a dose by more than 16 weeks were nearly four times more likely to suffer vertebral fractures, compared with those who received on-time injections, according to the study, which was published in Annals of Internal Medicine.

“Because patients who used denosumab were at high risk for vertebral fracture, strategies to improve timely administration of denosumab in routine clinical settings are needed,” wrote the study authors, led by Houchen Lyu, MD, PhD, of National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation at General Hospital of Chinese PLA in Beijing.

Denosumab, a human monoclonal antibody, is used to reduce bone loss in osteoporosis. The manufacturer of Prolia, a brand of the drug, recommends it be given every 6 months, but the study reports that it’s common for injections to be delayed.

Researchers have linked cessation of denosumab to higher risk of fractures, and Dr. Lyu led a study published earlier this year that linked less-frequent doses to less bone mineral density improvement. “However,” the authors of the new study wrote, “whether delaying subsequent injections beyond the recommended 6-month interval is associated with fractures is unknown.”

For their new study, researchers retrospectively analyzed data from 2,594 patients in the U.K. 45 years or older (mean age, 76; 94% female; 53% with a history of major osteoporotic fracture) who began taking denosumab between 2010 and 2019. They used a design that aimed to emulate a clinical trial, comparing three dosing intervals: “on time” (within 4 weeks of the recommended 6-month interval), “short delay” (within 4-16 weeks) and “long delay” (16 weeks to 6 months).

The study found that the risk of composite fracture over 6 months out of 1,000 was 27.3 for on-time dosing, 32.2 for short-delay dosing, and 42.4 for long-delay dosing. The hazard ratio for long-delay versus on-time was 1.44 (95% confidence interval, 0.96-2.17; P = .093).

Vertebral fractures were less likely, but delays boosted the risk significantly: Over 6 months, it grew from 2.2 in 1,000 (on time) to 3.6 in 1,000 (short delay) and 10.1 in 1,000 (long delay). The HR for long delay versus on time was 3.91 (95% CI, 1.62-9.45; P = .005).

“This study had limited statistical power for composite fracture and several secondary end points ... except for vertebral fracture. Thus, evidence was insufficient to conclude that fracture risk was increased at other anatomical sites.”

In an accompanying editorial, two physicians from the University of Minnesota, Minneapolis, noted that the study is “timely and relevant” since the coronavirus pandemic may disrupt dosage schedules more than usual. While the study has limitations, the “findings are consistent with known denosumab pharmacokinetics and prior studies of fracture incidence after denosumab treatment discontinuation, wrote Kristine E. Ensrud, MD, MPH, who is also of Minneapolis VA Health Care System, and John T. Schousboe, MD, PhD, who is also of HealthPartners Institute.

The editorial authors noted that, in light of the pandemic, “some organizations recommend temporary transition to an oral bisphosphonate in patients receiving denosumab treatment for whom continued treatment is not feasible within 7 to 8 months of their most recent injection.”

In an interview, endocrinologist and osteoporosis specialist Ethel Siris, MD, of Columbia University, New York, said many of her patients aren’t coming in for denosumab injections during the pandemic. “It’s hard enough to get people to show up every 6 months to get their shot when things are going nicely,” she said. “We’re talking older women who may be on a lot of other medications. People forget, and it’s difficult for the office to constantly remind some of them to get their shots at an infusion center.”

The lack of symptoms is another challenge to getting patients to return for doses, she said. “In osteoporosis, the only time something hurts is if you break it.”

Since the pandemic began, many patients have been avoiding medical offices because of fear of getting the coronavirus.

The new research is helpful because it shows that patients are “more likely to fracture if they delay,” Dr. Siris noted. The endocrinologist added that she has successfully convinced some patients to give themselves subcutaneous injections in the abdomen at home.

Dr. Siris said she has been able to watch patients do these injections on video to check their technique. Her patients have been impressed by “how easy it is and delighted to have accomplished it,” she said.

The study was funded by the National Institutes of Health China’s National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation. The study authors, commentary authors, and Dr. Siris report no relevant disclosures.
 

SOURCE: Lyu H et al. Ann Intern Med. 2020 Jul 28. doi: 10.7326/M20-0882.

Delaying doses of denosumab after the first injection dramatically boosts the risk that patients with osteoporosis will suffer vertebral fractures, a new study confirms. Physicians say they are especially concerned about the risk facing patients who are delaying the treatment during the coronavirus pandemic.

doble-d/Getty Images

The recommended doses of denosumab are at 6-month intervals. Patients who delayed a dose by more than 16 weeks were nearly four times more likely to suffer vertebral fractures, compared with those who received on-time injections, according to the study, which was published in Annals of Internal Medicine.

“Because patients who used denosumab were at high risk for vertebral fracture, strategies to improve timely administration of denosumab in routine clinical settings are needed,” wrote the study authors, led by Houchen Lyu, MD, PhD, of National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation at General Hospital of Chinese PLA in Beijing.

Denosumab, a human monoclonal antibody, is used to reduce bone loss in osteoporosis. The manufacturer of Prolia, a brand of the drug, recommends it be given every 6 months, but the study reports that it’s common for injections to be delayed.

Researchers have linked cessation of denosumab to higher risk of fractures, and Dr. Lyu led a study published earlier this year that linked less-frequent doses to less bone mineral density improvement. “However,” the authors of the new study wrote, “whether delaying subsequent injections beyond the recommended 6-month interval is associated with fractures is unknown.”

For their new study, researchers retrospectively analyzed data from 2,594 patients in the U.K. 45 years or older (mean age, 76; 94% female; 53% with a history of major osteoporotic fracture) who began taking denosumab between 2010 and 2019. They used a design that aimed to emulate a clinical trial, comparing three dosing intervals: “on time” (within 4 weeks of the recommended 6-month interval), “short delay” (within 4-16 weeks) and “long delay” (16 weeks to 6 months).

The study found that the risk of composite fracture over 6 months out of 1,000 was 27.3 for on-time dosing, 32.2 for short-delay dosing, and 42.4 for long-delay dosing. The hazard ratio for long-delay versus on-time was 1.44 (95% confidence interval, 0.96-2.17; P = .093).

Vertebral fractures were less likely, but delays boosted the risk significantly: Over 6 months, it grew from 2.2 in 1,000 (on time) to 3.6 in 1,000 (short delay) and 10.1 in 1,000 (long delay). The HR for long delay versus on time was 3.91 (95% CI, 1.62-9.45; P = .005).

“This study had limited statistical power for composite fracture and several secondary end points ... except for vertebral fracture. Thus, evidence was insufficient to conclude that fracture risk was increased at other anatomical sites.”

In an accompanying editorial, two physicians from the University of Minnesota, Minneapolis, noted that the study is “timely and relevant” since the coronavirus pandemic may disrupt dosage schedules more than usual. While the study has limitations, the “findings are consistent with known denosumab pharmacokinetics and prior studies of fracture incidence after denosumab treatment discontinuation, wrote Kristine E. Ensrud, MD, MPH, who is also of Minneapolis VA Health Care System, and John T. Schousboe, MD, PhD, who is also of HealthPartners Institute.

The editorial authors noted that, in light of the pandemic, “some organizations recommend temporary transition to an oral bisphosphonate in patients receiving denosumab treatment for whom continued treatment is not feasible within 7 to 8 months of their most recent injection.”

In an interview, endocrinologist and osteoporosis specialist Ethel Siris, MD, of Columbia University, New York, said many of her patients aren’t coming in for denosumab injections during the pandemic. “It’s hard enough to get people to show up every 6 months to get their shot when things are going nicely,” she said. “We’re talking older women who may be on a lot of other medications. People forget, and it’s difficult for the office to constantly remind some of them to get their shots at an infusion center.”

The lack of symptoms is another challenge to getting patients to return for doses, she said. “In osteoporosis, the only time something hurts is if you break it.”

Since the pandemic began, many patients have been avoiding medical offices because of fear of getting the coronavirus.

The new research is helpful because it shows that patients are “more likely to fracture if they delay,” Dr. Siris noted. The endocrinologist added that she has successfully convinced some patients to give themselves subcutaneous injections in the abdomen at home.

Dr. Siris said she has been able to watch patients do these injections on video to check their technique. Her patients have been impressed by “how easy it is and delighted to have accomplished it,” she said.

The study was funded by the National Institutes of Health China’s National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation. The study authors, commentary authors, and Dr. Siris report no relevant disclosures.
 

SOURCE: Lyu H et al. Ann Intern Med. 2020 Jul 28. doi: 10.7326/M20-0882.

New data from the National Institutes of Health–funded Osteoarthritis Initiative suggest that, in some women at least, taking bisphosphonates may help to reduce the chances that there will be radiographic progression of knee osteoarthritis (OA).

decade3d/Thinkstock

In a propensity-matched cohort analysis, women who had a Kellgren and Lawrence (KL) grade of less than 2 and who used bisphosphonates were half as likely as those who did not use bisphosphonates to have radiographic OA progression at 2 years (hazard ratio, 0.53; 95% confidence interval, 0.35-0.79). Radiographic OA progression has been defined as a one-step increase in the KL grade.

While the association appeared even stronger in women with a KL grade less than 2 and who were not overweight (HR, 0.49; 95% CI, 0.26-0.92), bisphosphonate use was not associated with radiographic OA progression in women with a higher (≥2) KL grade (HR, 1.06; 95% CI, 0.83-1.35).

“In all analyses, the effect of bisphosphonates was larger in radiographic-disease-naive individuals, suggesting protection using bisphosphonates may be more profound in those who do not already have evidence of knee damage or who have mild disease, and once damage occurs, bisphosphonate use may not have much effect,” Kaleen N. Hayes, PharmD, of the University of Toronto and her coauthors reported in the Journal of Bone and Mineral Research.

“Our study was the first to our knowledge to examine bisphosphonate exposure effects in different disease severity subgroups and obesity classifications using a rigorous, propensity-matched time-to-event analysis that uniquely addresses confounding by indication,” Dr. Hayes and her team wrote.

Furthermore, they noted that extensive sensitivity analyses, which included redoing the primary analyses to look at statin use, showed that their main conclusions were unchanged and that this helped account for any potential residual confounding, healthy-user bias, or exposure misclassification.
 

Study details

The Osteoarthritis Initiative is a 10-year longitudinal cohort study conducted at four clinical sites in the United States and recruited men and women aged 45-75 years over a 2-year period starting in 2004. Dr. Hayes and her coauthors restricted their analyses to women 50 years and older. Their study population consisted of 344 bisphosphonate users and 344 bisphosphonate nonusers.

The main bisphosphonate being taken was alendronate (69%), and the average duration of bisphosphonate use was 3.3 years, but no significant effect of duration of use on radiographic progression was found.

The women were followed until the first radiographic OA progression, or the first missed visit or end of the 2-year follow-up period.

Overall, 95 (13.8%) of the 688 women included in the analysis experienced radiographic OA progression. Of those, 27 (3.9%) had a KL grade of less than 2 and 68 (9.8%) had a KL grade of 2 or greater. Ten women with KL less than 2 and 27 women with KL or 2 or greater were taking bisphosphonates at their baseline visit.

“Kaplan-Meier analysis indicated that non-users and users with a baseline KL grade of 0 or 1 had 2-year risks of progression of 10.5% and 5.9%, respectively, whereas non-users and users with a baseline KL grade of 2 or 3 had 2-year of these women risks of progression of 23.0% and 23.5%, respectively,” reported the authors.

Before propensity score matching, Dr. Hayes and her colleagues observed that women taking bisphosphonates were older, had lower body weight and a higher prevalence of any fracture or hip and vertebral fractures, and were also more likely be White, compared with non-users. “In addition, bisphosphonate-users appeared to be healthier than non-users, as suggested by a lower smoking prevalence, lower average baseline KL grade, lower diabetes prevalence, and higher multivitamin use (a healthy-user proxy),” they acknowledged.

Results in perspective

“The key thing that I’m concerned about when I see something like bisphosphonates and osteoarthritis is just how well confounding has been addressed,” commented Tuhina Neogi, MD, PhD, professor of medicine and epidemiology at Boston University and chief of rheumatology at Boston Medical Center, in an interview.

“So are there factors other than the bisphosphonates themselves that might explain the findings? It looks like they’ve taken into account a lot of important things that one would consider for trying to get the two groups to look as similar as possible,” she added. Dr. Neogi queried, however, if body mass index had been suitably been adjusted for even after propensity score matching.

“The effect estimate is quite large, so I do think there is some confounding. So I would feel comfortable saying that there’s a signal here for bisphosphonates in reducing the risk of progression among those who do not have radiographic OA at baseline,” Dr. Neogi observed.

“The context of all this is that there have been large, well-designed, randomized control trials of oral bisphosphonates from years ago that did not find any benefit of bisphosphonates in [terms of] radiographic OA progression,” Dr. Neogi explained.

In the Knee OA Structural Arthritis (KOSTAR) study, now considered “quite a large landmark study,” the efficacy of risedronate in providing symptom relief and slowing disease progression was studied in almost 2,500 patients. “They saw some improvements in signs and symptoms, but risedronate did not significantly reduce radiographic progression. [However] there were some signals on biomarkers,” Dr. Neogi said.

One of the issues is that radiographs are too insensitive to pick up early bone changes in OA, a fact not missed by Dr. Hayes et al. More recent research has thus looked to using more sensitive imaging methods, such as CT and MRI, such as a recent study published in JAMA looking at the use of intravenous zoledronic acid on bone marrow lesions and cartilage volume. The results did not show any benefit of bisphosphonate use over 2 years.

“So even though we thought the MRI might provide a better way to detect a signal, it hasn’t panned out,” Dr. Neogi said.

But that’s not to say that there isn’t still a signal. Dr. Neogi’s most recent research has been using MRI to look at bone marrow lesion volume in women who were newly starting bisphosphonate therapy versus those who were not, and this has been just been accepted for publication.

“We found no difference in bone marrow lesion volume between the two groups. But in the women who had bone marrow lesions at baseline, there was a statistically significant greater proportion of women on bisphosphonates having a decrease in bone marrow lesion volume than the non-initiators,” she said.

So is there evidence that putting more women on bisphosphonates could prevent OA? “I’m not sure that you would be able to say that this should be something that all postmenopausal women should be on,” Dr. Neogi said.

“There’s a theoretical risk that has not been formally studied that, if you diminish bone turnover and you get more and more mineralization occurring, the bone potentially may have altered mechanical properties, become stiffer and, over the long term, that might not be good for OA.”

She added that, if there is already a clear clinical indication for bisphosphonate use, however, such as older women who have had a fracture and who should be on a bisphosphonate anyway, then “a bisphosphonate has the theoretical potential additional benefit for their osteoarthritis.”

The authors and Dr. Neogi had no conflicts of interest or relationships to disclose.

SOURCE: Hayes KN et al. J Bone Miner Res. 2020 July 14. doi: 10.1002/jbmr.4133.
 

New data from the National Institutes of Health–funded Osteoarthritis Initiative suggest that, in some women at least, taking bisphosphonates may help to reduce the chances that there will be radiographic progression of knee osteoarthritis (OA).

decade3d/Thinkstock

In a propensity-matched cohort analysis, women who had a Kellgren and Lawrence (KL) grade of less than 2 and who used bisphosphonates were half as likely as those who did not use bisphosphonates to have radiographic OA progression at 2 years (hazard ratio, 0.53; 95% confidence interval, 0.35-0.79). Radiographic OA progression has been defined as a one-step increase in the KL grade.

While the association appeared even stronger in women with a KL grade less than 2 and who were not overweight (HR, 0.49; 95% CI, 0.26-0.92), bisphosphonate use was not associated with radiographic OA progression in women with a higher (≥2) KL grade (HR, 1.06; 95% CI, 0.83-1.35).

“In all analyses, the effect of bisphosphonates was larger in radiographic-disease-naive individuals, suggesting protection using bisphosphonates may be more profound in those who do not already have evidence of knee damage or who have mild disease, and once damage occurs, bisphosphonate use may not have much effect,” Kaleen N. Hayes, PharmD, of the University of Toronto and her coauthors reported in the Journal of Bone and Mineral Research.

“Our study was the first to our knowledge to examine bisphosphonate exposure effects in different disease severity subgroups and obesity classifications using a rigorous, propensity-matched time-to-event analysis that uniquely addresses confounding by indication,” Dr. Hayes and her team wrote.

Furthermore, they noted that extensive sensitivity analyses, which included redoing the primary analyses to look at statin use, showed that their main conclusions were unchanged and that this helped account for any potential residual confounding, healthy-user bias, or exposure misclassification.
 

Study details

The Osteoarthritis Initiative is a 10-year longitudinal cohort study conducted at four clinical sites in the United States and recruited men and women aged 45-75 years over a 2-year period starting in 2004. Dr. Hayes and her coauthors restricted their analyses to women 50 years and older. Their study population consisted of 344 bisphosphonate users and 344 bisphosphonate nonusers.

The main bisphosphonate being taken was alendronate (69%), and the average duration of bisphosphonate use was 3.3 years, but no significant effect of duration of use on radiographic progression was found.

The women were followed until the first radiographic OA progression, or the first missed visit or end of the 2-year follow-up period.

Overall, 95 (13.8%) of the 688 women included in the analysis experienced radiographic OA progression. Of those, 27 (3.9%) had a KL grade of less than 2 and 68 (9.8%) had a KL grade of 2 or greater. Ten women with KL less than 2 and 27 women with KL or 2 or greater were taking bisphosphonates at their baseline visit.

“Kaplan-Meier analysis indicated that non-users and users with a baseline KL grade of 0 or 1 had 2-year risks of progression of 10.5% and 5.9%, respectively, whereas non-users and users with a baseline KL grade of 2 or 3 had 2-year of these women risks of progression of 23.0% and 23.5%, respectively,” reported the authors.

Before propensity score matching, Dr. Hayes and her colleagues observed that women taking bisphosphonates were older, had lower body weight and a higher prevalence of any fracture or hip and vertebral fractures, and were also more likely be White, compared with non-users. “In addition, bisphosphonate-users appeared to be healthier than non-users, as suggested by a lower smoking prevalence, lower average baseline KL grade, lower diabetes prevalence, and higher multivitamin use (a healthy-user proxy),” they acknowledged.

Results in perspective

“The key thing that I’m concerned about when I see something like bisphosphonates and osteoarthritis is just how well confounding has been addressed,” commented Tuhina Neogi, MD, PhD, professor of medicine and epidemiology at Boston University and chief of rheumatology at Boston Medical Center, in an interview.

“So are there factors other than the bisphosphonates themselves that might explain the findings? It looks like they’ve taken into account a lot of important things that one would consider for trying to get the two groups to look as similar as possible,” she added. Dr. Neogi queried, however, if body mass index had been suitably been adjusted for even after propensity score matching.

“The effect estimate is quite large, so I do think there is some confounding. So I would feel comfortable saying that there’s a signal here for bisphosphonates in reducing the risk of progression among those who do not have radiographic OA at baseline,” Dr. Neogi observed.

“The context of all this is that there have been large, well-designed, randomized control trials of oral bisphosphonates from years ago that did not find any benefit of bisphosphonates in [terms of] radiographic OA progression,” Dr. Neogi explained.

In the Knee OA Structural Arthritis (KOSTAR) study, now considered “quite a large landmark study,” the efficacy of risedronate in providing symptom relief and slowing disease progression was studied in almost 2,500 patients. “They saw some improvements in signs and symptoms, but risedronate did not significantly reduce radiographic progression. [However] there were some signals on biomarkers,” Dr. Neogi said.

One of the issues is that radiographs are too insensitive to pick up early bone changes in OA, a fact not missed by Dr. Hayes et al. More recent research has thus looked to using more sensitive imaging methods, such as CT and MRI, such as a recent study published in JAMA looking at the use of intravenous zoledronic acid on bone marrow lesions and cartilage volume. The results did not show any benefit of bisphosphonate use over 2 years.

“So even though we thought the MRI might provide a better way to detect a signal, it hasn’t panned out,” Dr. Neogi said.

But that’s not to say that there isn’t still a signal. Dr. Neogi’s most recent research has been using MRI to look at bone marrow lesion volume in women who were newly starting bisphosphonate therapy versus those who were not, and this has been just been accepted for publication.

“We found no difference in bone marrow lesion volume between the two groups. But in the women who had bone marrow lesions at baseline, there was a statistically significant greater proportion of women on bisphosphonates having a decrease in bone marrow lesion volume than the non-initiators,” she said.

So is there evidence that putting more women on bisphosphonates could prevent OA? “I’m not sure that you would be able to say that this should be something that all postmenopausal women should be on,” Dr. Neogi said.

“There’s a theoretical risk that has not been formally studied that, if you diminish bone turnover and you get more and more mineralization occurring, the bone potentially may have altered mechanical properties, become stiffer and, over the long term, that might not be good for OA.”

She added that, if there is already a clear clinical indication for bisphosphonate use, however, such as older women who have had a fracture and who should be on a bisphosphonate anyway, then “a bisphosphonate has the theoretical potential additional benefit for their osteoarthritis.”

The authors and Dr. Neogi had no conflicts of interest or relationships to disclose.

SOURCE: Hayes KN et al. J Bone Miner Res. 2020 July 14. doi: 10.1002/jbmr.4133.
 

New data from the National Institutes of Health–funded Osteoarthritis Initiative suggest that, in some women at least, taking bisphosphonates may help to reduce the chances that there will be radiographic progression of knee osteoarthritis (OA).

decade3d/Thinkstock

In a propensity-matched cohort analysis, women who had a Kellgren and Lawrence (KL) grade of less than 2 and who used bisphosphonates were half as likely as those who did not use bisphosphonates to have radiographic OA progression at 2 years (hazard ratio, 0.53; 95% confidence interval, 0.35-0.79). Radiographic OA progression has been defined as a one-step increase in the KL grade.

While the association appeared even stronger in women with a KL grade less than 2 and who were not overweight (HR, 0.49; 95% CI, 0.26-0.92), bisphosphonate use was not associated with radiographic OA progression in women with a higher (≥2) KL grade (HR, 1.06; 95% CI, 0.83-1.35).

“In all analyses, the effect of bisphosphonates was larger in radiographic-disease-naive individuals, suggesting protection using bisphosphonates may be more profound in those who do not already have evidence of knee damage or who have mild disease, and once damage occurs, bisphosphonate use may not have much effect,” Kaleen N. Hayes, PharmD, of the University of Toronto and her coauthors reported in the Journal of Bone and Mineral Research.

“Our study was the first to our knowledge to examine bisphosphonate exposure effects in different disease severity subgroups and obesity classifications using a rigorous, propensity-matched time-to-event analysis that uniquely addresses confounding by indication,” Dr. Hayes and her team wrote.

Furthermore, they noted that extensive sensitivity analyses, which included redoing the primary analyses to look at statin use, showed that their main conclusions were unchanged and that this helped account for any potential residual confounding, healthy-user bias, or exposure misclassification.
 

Study details

The Osteoarthritis Initiative is a 10-year longitudinal cohort study conducted at four clinical sites in the United States and recruited men and women aged 45-75 years over a 2-year period starting in 2004. Dr. Hayes and her coauthors restricted their analyses to women 50 years and older. Their study population consisted of 344 bisphosphonate users and 344 bisphosphonate nonusers.

The main bisphosphonate being taken was alendronate (69%), and the average duration of bisphosphonate use was 3.3 years, but no significant effect of duration of use on radiographic progression was found.

The women were followed until the first radiographic OA progression, or the first missed visit or end of the 2-year follow-up period.

Overall, 95 (13.8%) of the 688 women included in the analysis experienced radiographic OA progression. Of those, 27 (3.9%) had a KL grade of less than 2 and 68 (9.8%) had a KL grade of 2 or greater. Ten women with KL less than 2 and 27 women with KL or 2 or greater were taking bisphosphonates at their baseline visit.

“Kaplan-Meier analysis indicated that non-users and users with a baseline KL grade of 0 or 1 had 2-year risks of progression of 10.5% and 5.9%, respectively, whereas non-users and users with a baseline KL grade of 2 or 3 had 2-year of these women risks of progression of 23.0% and 23.5%, respectively,” reported the authors.

Before propensity score matching, Dr. Hayes and her colleagues observed that women taking bisphosphonates were older, had lower body weight and a higher prevalence of any fracture or hip and vertebral fractures, and were also more likely be White, compared with non-users. “In addition, bisphosphonate-users appeared to be healthier than non-users, as suggested by a lower smoking prevalence, lower average baseline KL grade, lower diabetes prevalence, and higher multivitamin use (a healthy-user proxy),” they acknowledged.

Results in perspective

“The key thing that I’m concerned about when I see something like bisphosphonates and osteoarthritis is just how well confounding has been addressed,” commented Tuhina Neogi, MD, PhD, professor of medicine and epidemiology at Boston University and chief of rheumatology at Boston Medical Center, in an interview.

“So are there factors other than the bisphosphonates themselves that might explain the findings? It looks like they’ve taken into account a lot of important things that one would consider for trying to get the two groups to look as similar as possible,” she added. Dr. Neogi queried, however, if body mass index had been suitably been adjusted for even after propensity score matching.

“The effect estimate is quite large, so I do think there is some confounding. So I would feel comfortable saying that there’s a signal here for bisphosphonates in reducing the risk of progression among those who do not have radiographic OA at baseline,” Dr. Neogi observed.

“The context of all this is that there have been large, well-designed, randomized control trials of oral bisphosphonates from years ago that did not find any benefit of bisphosphonates in [terms of] radiographic OA progression,” Dr. Neogi explained.

In the Knee OA Structural Arthritis (KOSTAR) study, now considered “quite a large landmark study,” the efficacy of risedronate in providing symptom relief and slowing disease progression was studied in almost 2,500 patients. “They saw some improvements in signs and symptoms, but risedronate did not significantly reduce radiographic progression. [However] there were some signals on biomarkers,” Dr. Neogi said.

One of the issues is that radiographs are too insensitive to pick up early bone changes in OA, a fact not missed by Dr. Hayes et al. More recent research has thus looked to using more sensitive imaging methods, such as CT and MRI, such as a recent study published in JAMA looking at the use of intravenous zoledronic acid on bone marrow lesions and cartilage volume. The results did not show any benefit of bisphosphonate use over 2 years.

“So even though we thought the MRI might provide a better way to detect a signal, it hasn’t panned out,” Dr. Neogi said.

But that’s not to say that there isn’t still a signal. Dr. Neogi’s most recent research has been using MRI to look at bone marrow lesion volume in women who were newly starting bisphosphonate therapy versus those who were not, and this has been just been accepted for publication.

“We found no difference in bone marrow lesion volume between the two groups. But in the women who had bone marrow lesions at baseline, there was a statistically significant greater proportion of women on bisphosphonates having a decrease in bone marrow lesion volume than the non-initiators,” she said.

So is there evidence that putting more women on bisphosphonates could prevent OA? “I’m not sure that you would be able to say that this should be something that all postmenopausal women should be on,” Dr. Neogi said.

“There’s a theoretical risk that has not been formally studied that, if you diminish bone turnover and you get more and more mineralization occurring, the bone potentially may have altered mechanical properties, become stiffer and, over the long term, that might not be good for OA.”

She added that, if there is already a clear clinical indication for bisphosphonate use, however, such as older women who have had a fracture and who should be on a bisphosphonate anyway, then “a bisphosphonate has the theoretical potential additional benefit for their osteoarthritis.”

The authors and Dr. Neogi had no conflicts of interest or relationships to disclose.

SOURCE: Hayes KN et al. J Bone Miner Res. 2020 July 14. doi: 10.1002/jbmr.4133.
 

Recommendations on use of the new dual-action anabolic agent romosozumab (Evenity, Amgen) and how to safely transition between osteoporosis agents are two of the issues addressed in the latest clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis from the American Association of Clinical Endocrinologists and American College of Endocrinology.

“This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of postmenopausal osteoporosis,” the authors wrote.

The guidelines focus on 12 key clinical questions related to postmenopausal osteoporosis, with 52 specific recommendations, each graded according to the level of evidence.

They also include a treatment algorithm to help guide choice of therapy.
 

Reiterating role of FRAX in the diagnosis of patients with osteopenia

Among key updates is an emphasis on the role of the Fracture Risk Assessment Tool (FRAX) in the diagnosis of osteoporosis in patients with osteopenia.

While patients have traditionally been diagnosed with osteoporosis based on the presence of low bone mineral density (BMD) in the absence of fracture, the updated guidelines indicate that osteoporosis may be diagnosed in patients with osteopenia and an increased fracture risk using FRAX.

“The use of FRAX and osteopenia to diagnosis osteoporosis was first proposed by the National Bone Health Alliance years ago, and in the 2016 guideline, we agreed with it,” Pauline M. Camacho, MD, cochair of the guidelines task force, said in an interview.

“We reiterate in the 2020 guideline that we feel this is a valid diagnostic criteria,” said Dr. Camacho, professor of medicine and director of the Osteoporosis and Metabolic Bone Disease Center at Loyola University Chicago, Maywood, Ill. “It makes sense because when the thresholds are met by FRAX in patients with osteopenia, treatment is recommended. Therefore, why would they not fulfill treatment criteria for diagnosing osteoporosis?”

An increased risk of fracture based on a FRAX score may also be used to determine pharmacologic therapy, as can other traditional factors such as a low T score or a fragility fracture, the guidelines stated.
 

High risk vs. very high risk guides choice of first therapy

Another key update is the clarification of the risk stratification of patients who are high risk versus very high risk, which is key in determining the initial choice of agents and duration of therapy.

Specifically, patients should be considered at a very high fracture risk if they have the following criteria: a recent fracture (e.g., within the past 12 months), fractures while on approved osteoporosis therapy, multiple fractures, fractures while on drugs causing skeletal harm (e.g., long-term glucocorticoids), very low T score (e.g., less than −3.0), a high risk for falls or history of injurious falls, and a very high fracture probability by FRAX (e.g., major osteoporosis fracture >30%, hip fracture >4.5%) or other validated fracture risk algorithm.

Meanwhile, patients should be considered at high risk if they have been diagnosed with osteoporosis but do not meet the criteria for very high fracture risk.
 

Romosozumab brought into the mix

Another important update provides information on the role of one of the newest osteoporosis agents on the market, the anabolic drug romosozumab, a monoclonal antibody directed against sclerostin.

The drug’s approval by the Food and Drug Administration in 2019 for postmenopausal women at high risk of fracture was based on two large trials that showed dramatic increases in bone density through modeling as well as remodeling.

Those studies specifically showed significant reductions in radiographic vertebral fractures with romosozumab, compared with placebo and alendronate.

Dr. Camacho noted that romosozumab “will likely be for the very high risk group and those who have maxed out on teriparatide or abaloparatide.”

Romosozumab can safely be used in patients with prior radiation exposure, the guidelines noted.

Importantly, because of reports of a higher risk of serious cardiovascular events with romosozumab, compared with alendronate, romosozumab comes with a black-box warning that it should not be used in patients at high risk for cardiovascular events or who have had a recent myocardial infarction or stroke.

“Unfortunately, the very high risk group is often the older patients,” Dr. Camacho noted.

“The drug should not be given if there is a history of myocardial infarction or stroke in the past year,” she emphasized. “Clinical judgment is needed to decide who is at risk for cardiovascular complications.”

Notably, teriparatide and abaloparatide have black box warnings of their own regarding risk for osteosarcoma.

Switching therapies

Reflecting the evolving data on osteoporosis drug holidays, the guidelines also addressed the issue and the clinical challenges of switching therapies.

“In 2016, we said drug holidays are not recommended, and the treatment can be continued indefinitely, [however] in 2020, we felt that if some patients are no longer high risk, they can be transitioned off the drug,” Dr. Camacho said.

For teriparatide and abaloparatide, the FDA recommends treatment be limited to no more than 2 years, and for romosozumab, 1 year.

The updated guidelines recommend that upon discontinuation of an anabolic agent (e.g., abaloparatide, romosozumab, or teriparatide), a switch to therapy with an antiresorptive agent, such as denosumab or bisphosphonates, should be implemented to prevent loss of BMD and fracture efficacy.

Discontinuation of denosumab, however, can have notably negative effects. Clinical trials show rapid decreases in BMD when denosumab treatment is stopped after 2 or 8 years, as well as rapid loss of protection from vertebral fractures.

Therefore, if denosumab is going to be discontinued, there should be a proper transition to an antiresorptive agent for a limited time, such as one infusion of the bisphosphonate zoledronate.
 

Communicate the risks with and without treatment to patients

The authors underscored that, in addition to communicating the potential risk and expected benefits of osteoporosis treatments, clinicians should make sure patients fully appreciate the risk of fractures and their consequences, such as pain, disability, loss of independence, and death, when no treatment is given.

“It is incumbent on the clinician to provide this information to each patient in a manner that is fully understood, and it is equally important to learn from the patient about cultural beliefs, previous treatment experiences, fears, and concerns,” they wrote.

And in estimating patients’ fracture risk, T score must be combined with clinical risk factors, particularly advanced age and previous fracture, and clinicians should recognize that the absolute fracture risk is more useful than a risk ratio in developing treatment plans.

“Treatment recommendations may be quite different; an early postmenopausal woman with a T score of −2.5 has osteoporosis, although fracture risk is much lower than an 80-year-old woman with the same T score,” the authors explained.

Dr. Camacho reported financial relationships with Amgen and Shire. Disclosures for other task force members are detailed in the guidelines.

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

Recommendations on use of the new dual-action anabolic agent romosozumab (Evenity, Amgen) and how to safely transition between osteoporosis agents are two of the issues addressed in the latest clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis from the American Association of Clinical Endocrinologists and American College of Endocrinology.

“This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of postmenopausal osteoporosis,” the authors wrote.

The guidelines focus on 12 key clinical questions related to postmenopausal osteoporosis, with 52 specific recommendations, each graded according to the level of evidence.

They also include a treatment algorithm to help guide choice of therapy.
 

Reiterating role of FRAX in the diagnosis of patients with osteopenia

Among key updates is an emphasis on the role of the Fracture Risk Assessment Tool (FRAX) in the diagnosis of osteoporosis in patients with osteopenia.

While patients have traditionally been diagnosed with osteoporosis based on the presence of low bone mineral density (BMD) in the absence of fracture, the updated guidelines indicate that osteoporosis may be diagnosed in patients with osteopenia and an increased fracture risk using FRAX.

“The use of FRAX and osteopenia to diagnosis osteoporosis was first proposed by the National Bone Health Alliance years ago, and in the 2016 guideline, we agreed with it,” Pauline M. Camacho, MD, cochair of the guidelines task force, said in an interview.

“We reiterate in the 2020 guideline that we feel this is a valid diagnostic criteria,” said Dr. Camacho, professor of medicine and director of the Osteoporosis and Metabolic Bone Disease Center at Loyola University Chicago, Maywood, Ill. “It makes sense because when the thresholds are met by FRAX in patients with osteopenia, treatment is recommended. Therefore, why would they not fulfill treatment criteria for diagnosing osteoporosis?”

An increased risk of fracture based on a FRAX score may also be used to determine pharmacologic therapy, as can other traditional factors such as a low T score or a fragility fracture, the guidelines stated.
 

High risk vs. very high risk guides choice of first therapy

Another key update is the clarification of the risk stratification of patients who are high risk versus very high risk, which is key in determining the initial choice of agents and duration of therapy.

Specifically, patients should be considered at a very high fracture risk if they have the following criteria: a recent fracture (e.g., within the past 12 months), fractures while on approved osteoporosis therapy, multiple fractures, fractures while on drugs causing skeletal harm (e.g., long-term glucocorticoids), very low T score (e.g., less than −3.0), a high risk for falls or history of injurious falls, and a very high fracture probability by FRAX (e.g., major osteoporosis fracture >30%, hip fracture >4.5%) or other validated fracture risk algorithm.

Meanwhile, patients should be considered at high risk if they have been diagnosed with osteoporosis but do not meet the criteria for very high fracture risk.
 

Romosozumab brought into the mix

Another important update provides information on the role of one of the newest osteoporosis agents on the market, the anabolic drug romosozumab, a monoclonal antibody directed against sclerostin.

The drug’s approval by the Food and Drug Administration in 2019 for postmenopausal women at high risk of fracture was based on two large trials that showed dramatic increases in bone density through modeling as well as remodeling.

Those studies specifically showed significant reductions in radiographic vertebral fractures with romosozumab, compared with placebo and alendronate.

Dr. Camacho noted that romosozumab “will likely be for the very high risk group and those who have maxed out on teriparatide or abaloparatide.”

Romosozumab can safely be used in patients with prior radiation exposure, the guidelines noted.

Importantly, because of reports of a higher risk of serious cardiovascular events with romosozumab, compared with alendronate, romosozumab comes with a black-box warning that it should not be used in patients at high risk for cardiovascular events or who have had a recent myocardial infarction or stroke.

“Unfortunately, the very high risk group is often the older patients,” Dr. Camacho noted.

“The drug should not be given if there is a history of myocardial infarction or stroke in the past year,” she emphasized. “Clinical judgment is needed to decide who is at risk for cardiovascular complications.”

Notably, teriparatide and abaloparatide have black box warnings of their own regarding risk for osteosarcoma.

Switching therapies

Reflecting the evolving data on osteoporosis drug holidays, the guidelines also addressed the issue and the clinical challenges of switching therapies.

“In 2016, we said drug holidays are not recommended, and the treatment can be continued indefinitely, [however] in 2020, we felt that if some patients are no longer high risk, they can be transitioned off the drug,” Dr. Camacho said.

For teriparatide and abaloparatide, the FDA recommends treatment be limited to no more than 2 years, and for romosozumab, 1 year.

The updated guidelines recommend that upon discontinuation of an anabolic agent (e.g., abaloparatide, romosozumab, or teriparatide), a switch to therapy with an antiresorptive agent, such as denosumab or bisphosphonates, should be implemented to prevent loss of BMD and fracture efficacy.

Discontinuation of denosumab, however, can have notably negative effects. Clinical trials show rapid decreases in BMD when denosumab treatment is stopped after 2 or 8 years, as well as rapid loss of protection from vertebral fractures.

Therefore, if denosumab is going to be discontinued, there should be a proper transition to an antiresorptive agent for a limited time, such as one infusion of the bisphosphonate zoledronate.
 

Communicate the risks with and without treatment to patients

The authors underscored that, in addition to communicating the potential risk and expected benefits of osteoporosis treatments, clinicians should make sure patients fully appreciate the risk of fractures and their consequences, such as pain, disability, loss of independence, and death, when no treatment is given.

“It is incumbent on the clinician to provide this information to each patient in a manner that is fully understood, and it is equally important to learn from the patient about cultural beliefs, previous treatment experiences, fears, and concerns,” they wrote.

And in estimating patients’ fracture risk, T score must be combined with clinical risk factors, particularly advanced age and previous fracture, and clinicians should recognize that the absolute fracture risk is more useful than a risk ratio in developing treatment plans.

“Treatment recommendations may be quite different; an early postmenopausal woman with a T score of −2.5 has osteoporosis, although fracture risk is much lower than an 80-year-old woman with the same T score,” the authors explained.

Dr. Camacho reported financial relationships with Amgen and Shire. Disclosures for other task force members are detailed in the guidelines.

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

Recommendations on use of the new dual-action anabolic agent romosozumab (Evenity, Amgen) and how to safely transition between osteoporosis agents are two of the issues addressed in the latest clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis from the American Association of Clinical Endocrinologists and American College of Endocrinology.

“This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of postmenopausal osteoporosis,” the authors wrote.

The guidelines focus on 12 key clinical questions related to postmenopausal osteoporosis, with 52 specific recommendations, each graded according to the level of evidence.

They also include a treatment algorithm to help guide choice of therapy.
 

Reiterating role of FRAX in the diagnosis of patients with osteopenia

Among key updates is an emphasis on the role of the Fracture Risk Assessment Tool (FRAX) in the diagnosis of osteoporosis in patients with osteopenia.

While patients have traditionally been diagnosed with osteoporosis based on the presence of low bone mineral density (BMD) in the absence of fracture, the updated guidelines indicate that osteoporosis may be diagnosed in patients with osteopenia and an increased fracture risk using FRAX.

“The use of FRAX and osteopenia to diagnosis osteoporosis was first proposed by the National Bone Health Alliance years ago, and in the 2016 guideline, we agreed with it,” Pauline M. Camacho, MD, cochair of the guidelines task force, said in an interview.

“We reiterate in the 2020 guideline that we feel this is a valid diagnostic criteria,” said Dr. Camacho, professor of medicine and director of the Osteoporosis and Metabolic Bone Disease Center at Loyola University Chicago, Maywood, Ill. “It makes sense because when the thresholds are met by FRAX in patients with osteopenia, treatment is recommended. Therefore, why would they not fulfill treatment criteria for diagnosing osteoporosis?”

An increased risk of fracture based on a FRAX score may also be used to determine pharmacologic therapy, as can other traditional factors such as a low T score or a fragility fracture, the guidelines stated.
 

High risk vs. very high risk guides choice of first therapy

Another key update is the clarification of the risk stratification of patients who are high risk versus very high risk, which is key in determining the initial choice of agents and duration of therapy.

Specifically, patients should be considered at a very high fracture risk if they have the following criteria: a recent fracture (e.g., within the past 12 months), fractures while on approved osteoporosis therapy, multiple fractures, fractures while on drugs causing skeletal harm (e.g., long-term glucocorticoids), very low T score (e.g., less than −3.0), a high risk for falls or history of injurious falls, and a very high fracture probability by FRAX (e.g., major osteoporosis fracture >30%, hip fracture >4.5%) or other validated fracture risk algorithm.

Meanwhile, patients should be considered at high risk if they have been diagnosed with osteoporosis but do not meet the criteria for very high fracture risk.
 

Romosozumab brought into the mix

Another important update provides information on the role of one of the newest osteoporosis agents on the market, the anabolic drug romosozumab, a monoclonal antibody directed against sclerostin.

The drug’s approval by the Food and Drug Administration in 2019 for postmenopausal women at high risk of fracture was based on two large trials that showed dramatic increases in bone density through modeling as well as remodeling.

Those studies specifically showed significant reductions in radiographic vertebral fractures with romosozumab, compared with placebo and alendronate.

Dr. Camacho noted that romosozumab “will likely be for the very high risk group and those who have maxed out on teriparatide or abaloparatide.”

Romosozumab can safely be used in patients with prior radiation exposure, the guidelines noted.

Importantly, because of reports of a higher risk of serious cardiovascular events with romosozumab, compared with alendronate, romosozumab comes with a black-box warning that it should not be used in patients at high risk for cardiovascular events or who have had a recent myocardial infarction or stroke.

“Unfortunately, the very high risk group is often the older patients,” Dr. Camacho noted.

“The drug should not be given if there is a history of myocardial infarction or stroke in the past year,” she emphasized. “Clinical judgment is needed to decide who is at risk for cardiovascular complications.”

Notably, teriparatide and abaloparatide have black box warnings of their own regarding risk for osteosarcoma.

Switching therapies

Reflecting the evolving data on osteoporosis drug holidays, the guidelines also addressed the issue and the clinical challenges of switching therapies.

“In 2016, we said drug holidays are not recommended, and the treatment can be continued indefinitely, [however] in 2020, we felt that if some patients are no longer high risk, they can be transitioned off the drug,” Dr. Camacho said.

For teriparatide and abaloparatide, the FDA recommends treatment be limited to no more than 2 years, and for romosozumab, 1 year.

The updated guidelines recommend that upon discontinuation of an anabolic agent (e.g., abaloparatide, romosozumab, or teriparatide), a switch to therapy with an antiresorptive agent, such as denosumab or bisphosphonates, should be implemented to prevent loss of BMD and fracture efficacy.

Discontinuation of denosumab, however, can have notably negative effects. Clinical trials show rapid decreases in BMD when denosumab treatment is stopped after 2 or 8 years, as well as rapid loss of protection from vertebral fractures.

Therefore, if denosumab is going to be discontinued, there should be a proper transition to an antiresorptive agent for a limited time, such as one infusion of the bisphosphonate zoledronate.
 

Communicate the risks with and without treatment to patients

The authors underscored that, in addition to communicating the potential risk and expected benefits of osteoporosis treatments, clinicians should make sure patients fully appreciate the risk of fractures and their consequences, such as pain, disability, loss of independence, and death, when no treatment is given.

“It is incumbent on the clinician to provide this information to each patient in a manner that is fully understood, and it is equally important to learn from the patient about cultural beliefs, previous treatment experiences, fears, and concerns,” they wrote.

And in estimating patients’ fracture risk, T score must be combined with clinical risk factors, particularly advanced age and previous fracture, and clinicians should recognize that the absolute fracture risk is more useful than a risk ratio in developing treatment plans.

“Treatment recommendations may be quite different; an early postmenopausal woman with a T score of −2.5 has osteoporosis, although fracture risk is much lower than an 80-year-old woman with the same T score,” the authors explained.

Dr. Camacho reported financial relationships with Amgen and Shire. Disclosures for other task force members are detailed in the guidelines.

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