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Tezepelumab effective in asthma with GERD
Among patients with asthma and comorbid gastroesophageal reflux disease (GERD), the PATHWAY and phase 3 NAVIGATOR clinical trials.
, according to a new post-hoc analysis of the phase 2bGERD occurs in about 60% of asthma patients, and the comorbidity is associated with a greater risk of asthma exacerbations. “As we start doing subgroup analyses, we are looking at different comorbidities and reflux is one that’s very common and very impactful on asthma outcomes in a negative way, so it became an area of interest,” said Njira Lugogo, MD, who presented the study during a poster session at the annual meeting of the American College of Chest Physicians (CHEST). She is a professor of internal medicine and pulmonary critical care at the University of Michigan, Ann Arbor.
The analysis confirmed other findings, with comorbid GERD associated with more exacerbations, use of maintenance steroids, and high-dose inhaled steroids. “They had more disease activity, and the effect [of tezepelumab treatment] was similar whether you had reflux or didn’t have reflux. It did seem like the people without reflux had a slightly higher reduction in exacerbations, so maybe there is a slight difference, but overall it looked like both groups were really improving,” said Dr. Lugogo.
Tezepelumab is a newer biologic, having received Food and Drug Administration approval in 2021. It targets the epithelial cytokine thymic stromal lymphopoietin (TSLP), which contributes allergic inflammatory responses by acting on various innate immune cells, including dendritic cells, mast cells, and CD34+ progenitor cells. It is upregulated in the airways of asthma patients, with higher levels linked to more severe disease. A single-nucleotide polymorphism in the gene that codes TSLP has also been found to be protective against asthma, atopic asthma, and airway hyper-responsiveness.
Dr. Lugogo noted that TSLP could be a factor in how GERD may worsen trigger or worsen asthma. It is produced in the epithelium of the upper airway in response to injury, which could include aspiration into bronchial tubes attributable to GERD, and this could lead to a downstream inflammatory and immune response. “Reducing the production of or at least blocking TSLP from an epithelium that’s being irritated by acid reflux could have potential benefits. On the reverse side, could the continued presence of reflux blunt the expected response [to tezepelumab]? If someone has very severe reflux, maybe you’ve treated their asthma with tezepelumab, and they’re still having symptoms. Could it be a masquerading issue [where] you have untreated reflux contributing to ongoing symptoms, which you’re attributing to not being related to asthma? So it’s looking at it in two different ways,” said Dr. Lugogo.
TSLP is the only biologic available to treat patients with non–type 2 inflammation, which includes about 10% of adult patients, according to Dr. Lugogo. Its mechanism also influences eosinophilic and allergic asthma. When tezepelumab first became available, Dr. Lugogo noticed that physicians tended to switch to it from another biologic rather than starting it up front, but that may be changing. “I feel like more and more people are starting it up front as a therapeutic intervention, so there seems to be more and more people embracing its use in the treatment of severe asthma,” she said.
The analysis included 294 patients with asthma and GERD and 1,040 with asthma alone. Patients in the GERD comorbidity group were older (55.0 versus 48.6 years), had a higher mean body mass index (30.8 versus 27.8), and were more likely to be female (67.3% versus 63.0%).
Maintenance oral corticosteroid use was higher in the GERD group (17.0% versus 6.9%), as was use of high inhaled corticosteroid dose (78.2% versus 67.0%), frequency of nasal polyps in the previous 2 years (21.4% versus 13.8%), and experience of more than two exacerbations in the previous year (42.2% versus 34.6%).
There was a 65% reduction (95% confidence interval, 50%-76%) in annualized asthma exacerbation rate versus placebo with tezepelumab treatment in the GERD group, compared with a 58% reduction in the asthma-only group (95% CI, 48%-66%). The drug led to a 0.10 increase in forced expiratory volume in 1 second versus placebo (95% CI, 0.00-0.19) at week 52 in the GERD group, versus 0.15 (95% CI, 0.10-0.20) in the asthma-only group. Tezepelumab also improved week 52 ACQ-6 scores in the GERD group (–0.39 versus placebo; 95% CI, –0.63 to –0.14) and the asthma-only group (–0.32 versus placebo; 95% CI, –0.45 to –0.19).
The study adds to the evidence supporting tezepelumab as a promising new therapy, according to Muhammad Adrish, MD, who attended the poster session and was asked to comment on the study. “I think that this is a very interesting analysis in the sense that gastric reflux disease is a frequent comorbid condition that we see in patients with asthma, and a lot of these patients can have poor outcomes. When you look at the results from the data, you see that regardless of how sick they were and how much medication utilization these patients have at baseline, they still had a pretty decent response to tezepelumab. That speaks to the efficacy of that drug along a wide spectrum of patients,” said Dr. Adrish, who is an associate professor of pulmonary, critical care, and sleep medicine at Baylor College of Medicine, Houston.
The PATHWAY and NAVIGATOR studies were funded by Amgen. Dr. Lugogo has advised or consulted for AstraZeneca, Amgen, Regeneron, TEVA, Avillion, Sanofi, Novartis, Genentech, GSK, and Janssen. Dr. Adrish has no relevant financial disclosures.
Among patients with asthma and comorbid gastroesophageal reflux disease (GERD), the PATHWAY and phase 3 NAVIGATOR clinical trials.
, according to a new post-hoc analysis of the phase 2bGERD occurs in about 60% of asthma patients, and the comorbidity is associated with a greater risk of asthma exacerbations. “As we start doing subgroup analyses, we are looking at different comorbidities and reflux is one that’s very common and very impactful on asthma outcomes in a negative way, so it became an area of interest,” said Njira Lugogo, MD, who presented the study during a poster session at the annual meeting of the American College of Chest Physicians (CHEST). She is a professor of internal medicine and pulmonary critical care at the University of Michigan, Ann Arbor.
The analysis confirmed other findings, with comorbid GERD associated with more exacerbations, use of maintenance steroids, and high-dose inhaled steroids. “They had more disease activity, and the effect [of tezepelumab treatment] was similar whether you had reflux or didn’t have reflux. It did seem like the people without reflux had a slightly higher reduction in exacerbations, so maybe there is a slight difference, but overall it looked like both groups were really improving,” said Dr. Lugogo.
Tezepelumab is a newer biologic, having received Food and Drug Administration approval in 2021. It targets the epithelial cytokine thymic stromal lymphopoietin (TSLP), which contributes allergic inflammatory responses by acting on various innate immune cells, including dendritic cells, mast cells, and CD34+ progenitor cells. It is upregulated in the airways of asthma patients, with higher levels linked to more severe disease. A single-nucleotide polymorphism in the gene that codes TSLP has also been found to be protective against asthma, atopic asthma, and airway hyper-responsiveness.
Dr. Lugogo noted that TSLP could be a factor in how GERD may worsen trigger or worsen asthma. It is produced in the epithelium of the upper airway in response to injury, which could include aspiration into bronchial tubes attributable to GERD, and this could lead to a downstream inflammatory and immune response. “Reducing the production of or at least blocking TSLP from an epithelium that’s being irritated by acid reflux could have potential benefits. On the reverse side, could the continued presence of reflux blunt the expected response [to tezepelumab]? If someone has very severe reflux, maybe you’ve treated their asthma with tezepelumab, and they’re still having symptoms. Could it be a masquerading issue [where] you have untreated reflux contributing to ongoing symptoms, which you’re attributing to not being related to asthma? So it’s looking at it in two different ways,” said Dr. Lugogo.
TSLP is the only biologic available to treat patients with non–type 2 inflammation, which includes about 10% of adult patients, according to Dr. Lugogo. Its mechanism also influences eosinophilic and allergic asthma. When tezepelumab first became available, Dr. Lugogo noticed that physicians tended to switch to it from another biologic rather than starting it up front, but that may be changing. “I feel like more and more people are starting it up front as a therapeutic intervention, so there seems to be more and more people embracing its use in the treatment of severe asthma,” she said.
The analysis included 294 patients with asthma and GERD and 1,040 with asthma alone. Patients in the GERD comorbidity group were older (55.0 versus 48.6 years), had a higher mean body mass index (30.8 versus 27.8), and were more likely to be female (67.3% versus 63.0%).
Maintenance oral corticosteroid use was higher in the GERD group (17.0% versus 6.9%), as was use of high inhaled corticosteroid dose (78.2% versus 67.0%), frequency of nasal polyps in the previous 2 years (21.4% versus 13.8%), and experience of more than two exacerbations in the previous year (42.2% versus 34.6%).
There was a 65% reduction (95% confidence interval, 50%-76%) in annualized asthma exacerbation rate versus placebo with tezepelumab treatment in the GERD group, compared with a 58% reduction in the asthma-only group (95% CI, 48%-66%). The drug led to a 0.10 increase in forced expiratory volume in 1 second versus placebo (95% CI, 0.00-0.19) at week 52 in the GERD group, versus 0.15 (95% CI, 0.10-0.20) in the asthma-only group. Tezepelumab also improved week 52 ACQ-6 scores in the GERD group (–0.39 versus placebo; 95% CI, –0.63 to –0.14) and the asthma-only group (–0.32 versus placebo; 95% CI, –0.45 to –0.19).
The study adds to the evidence supporting tezepelumab as a promising new therapy, according to Muhammad Adrish, MD, who attended the poster session and was asked to comment on the study. “I think that this is a very interesting analysis in the sense that gastric reflux disease is a frequent comorbid condition that we see in patients with asthma, and a lot of these patients can have poor outcomes. When you look at the results from the data, you see that regardless of how sick they were and how much medication utilization these patients have at baseline, they still had a pretty decent response to tezepelumab. That speaks to the efficacy of that drug along a wide spectrum of patients,” said Dr. Adrish, who is an associate professor of pulmonary, critical care, and sleep medicine at Baylor College of Medicine, Houston.
The PATHWAY and NAVIGATOR studies were funded by Amgen. Dr. Lugogo has advised or consulted for AstraZeneca, Amgen, Regeneron, TEVA, Avillion, Sanofi, Novartis, Genentech, GSK, and Janssen. Dr. Adrish has no relevant financial disclosures.
Among patients with asthma and comorbid gastroesophageal reflux disease (GERD), the PATHWAY and phase 3 NAVIGATOR clinical trials.
, according to a new post-hoc analysis of the phase 2bGERD occurs in about 60% of asthma patients, and the comorbidity is associated with a greater risk of asthma exacerbations. “As we start doing subgroup analyses, we are looking at different comorbidities and reflux is one that’s very common and very impactful on asthma outcomes in a negative way, so it became an area of interest,” said Njira Lugogo, MD, who presented the study during a poster session at the annual meeting of the American College of Chest Physicians (CHEST). She is a professor of internal medicine and pulmonary critical care at the University of Michigan, Ann Arbor.
The analysis confirmed other findings, with comorbid GERD associated with more exacerbations, use of maintenance steroids, and high-dose inhaled steroids. “They had more disease activity, and the effect [of tezepelumab treatment] was similar whether you had reflux or didn’t have reflux. It did seem like the people without reflux had a slightly higher reduction in exacerbations, so maybe there is a slight difference, but overall it looked like both groups were really improving,” said Dr. Lugogo.
Tezepelumab is a newer biologic, having received Food and Drug Administration approval in 2021. It targets the epithelial cytokine thymic stromal lymphopoietin (TSLP), which contributes allergic inflammatory responses by acting on various innate immune cells, including dendritic cells, mast cells, and CD34+ progenitor cells. It is upregulated in the airways of asthma patients, with higher levels linked to more severe disease. A single-nucleotide polymorphism in the gene that codes TSLP has also been found to be protective against asthma, atopic asthma, and airway hyper-responsiveness.
Dr. Lugogo noted that TSLP could be a factor in how GERD may worsen trigger or worsen asthma. It is produced in the epithelium of the upper airway in response to injury, which could include aspiration into bronchial tubes attributable to GERD, and this could lead to a downstream inflammatory and immune response. “Reducing the production of or at least blocking TSLP from an epithelium that’s being irritated by acid reflux could have potential benefits. On the reverse side, could the continued presence of reflux blunt the expected response [to tezepelumab]? If someone has very severe reflux, maybe you’ve treated their asthma with tezepelumab, and they’re still having symptoms. Could it be a masquerading issue [where] you have untreated reflux contributing to ongoing symptoms, which you’re attributing to not being related to asthma? So it’s looking at it in two different ways,” said Dr. Lugogo.
TSLP is the only biologic available to treat patients with non–type 2 inflammation, which includes about 10% of adult patients, according to Dr. Lugogo. Its mechanism also influences eosinophilic and allergic asthma. When tezepelumab first became available, Dr. Lugogo noticed that physicians tended to switch to it from another biologic rather than starting it up front, but that may be changing. “I feel like more and more people are starting it up front as a therapeutic intervention, so there seems to be more and more people embracing its use in the treatment of severe asthma,” she said.
The analysis included 294 patients with asthma and GERD and 1,040 with asthma alone. Patients in the GERD comorbidity group were older (55.0 versus 48.6 years), had a higher mean body mass index (30.8 versus 27.8), and were more likely to be female (67.3% versus 63.0%).
Maintenance oral corticosteroid use was higher in the GERD group (17.0% versus 6.9%), as was use of high inhaled corticosteroid dose (78.2% versus 67.0%), frequency of nasal polyps in the previous 2 years (21.4% versus 13.8%), and experience of more than two exacerbations in the previous year (42.2% versus 34.6%).
There was a 65% reduction (95% confidence interval, 50%-76%) in annualized asthma exacerbation rate versus placebo with tezepelumab treatment in the GERD group, compared with a 58% reduction in the asthma-only group (95% CI, 48%-66%). The drug led to a 0.10 increase in forced expiratory volume in 1 second versus placebo (95% CI, 0.00-0.19) at week 52 in the GERD group, versus 0.15 (95% CI, 0.10-0.20) in the asthma-only group. Tezepelumab also improved week 52 ACQ-6 scores in the GERD group (–0.39 versus placebo; 95% CI, –0.63 to –0.14) and the asthma-only group (–0.32 versus placebo; 95% CI, –0.45 to –0.19).
The study adds to the evidence supporting tezepelumab as a promising new therapy, according to Muhammad Adrish, MD, who attended the poster session and was asked to comment on the study. “I think that this is a very interesting analysis in the sense that gastric reflux disease is a frequent comorbid condition that we see in patients with asthma, and a lot of these patients can have poor outcomes. When you look at the results from the data, you see that regardless of how sick they were and how much medication utilization these patients have at baseline, they still had a pretty decent response to tezepelumab. That speaks to the efficacy of that drug along a wide spectrum of patients,” said Dr. Adrish, who is an associate professor of pulmonary, critical care, and sleep medicine at Baylor College of Medicine, Houston.
The PATHWAY and NAVIGATOR studies were funded by Amgen. Dr. Lugogo has advised or consulted for AstraZeneca, Amgen, Regeneron, TEVA, Avillion, Sanofi, Novartis, Genentech, GSK, and Janssen. Dr. Adrish has no relevant financial disclosures.
FROM CHEST 2023
Bariatric surgery, including sleeve gastrectomy, linked to fracture risk
VANCOUVER – Patients who undergo either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy are at an increased risk of fracture, compared with patients with obesity who do not undergo surgery, according to a new analysis of a predominantly male group of U.S. veterans.
Previous studies involving premenopausal women have found a risk of bone mineral density loss and fracture with bariatric surgery, but little was known about the risk among men. Research has also shown an increase in risk after RYGB, but there is less information on risks associated with sleeve gastrectomy, though it is now the most common surgery for weight loss.
Bone density loss after bariatric surgery has been shown to be significant, according to Eileen H. Koh, MD. “It’s quite a lot of bone loss, quickly,” said Dr. Koh, a graduated fellow from the endocrinology program at the University of California, San Francisco, who is moving to the University of Washington, Seattle.
Those observations generally come from studies of younger women. The purpose of the new study “was to see if we see the same risk of fracture in veterans who are older men, so kind of the opposite of the typical bariatric patient,” said Dr. Koh, who presented the research at the annual meeting of the American Society for Bone and Mineral Research.
The researchers analyzed data from 8,299 U.S. veterans who underwent sleeve gastrectomy (41%), RYGB (51%), adjustable gastric banding (4%), or an unspecified bariatric procedure (4%) between 2000 and 2020. They were matched with 24,877 individuals with obesity who did not undergo surgery. The investigators excluded individuals who were at high risk of fracture because of another condition, such as organ transplantation or dialysis. Men made up 70% of both surgical and nonsurgical groups. The mean age was 52 years for both, and 89% and 88% were not Hispanic or Latino, respectively. The proportion of White individuals was 72% and 64%, and the proportion of Black individuals was 18% and 24%.
After adjustment for demographic variables and comorbidities, bariatric surgery was associated with a 68% increased risk of fracture (hazard ratio, 1.68; 95% confidence interval, 1.57-1.80), including hip fractures (HR, 2.42; 95% CI, 1.98-2.97), spine (HR, 1.82; 95% CI, 1.61-2.06), radius/ulna (HR, 2.38; 95% CI, 2.05-2.77), humerus (HR, 1.56; 95% CI, 1.28-1.89), pelvis (HR, 2.41; 95% CI, 1.68-3.46), and tibia/fibula/ankle (HR, 1.50; 95% CI, 1.33-1.69). Increased fracture risk was associated with RYGB (HR, 1.93; 95% CI, 1.75-2.12) and sleeve gastrectomy (HR, 1.50; 95% CI, 1.33-1.69) but not adjustable gastric banding.
Compared with sleeve gastrectomy, adjustable gastric banding was associated with a decreased risk of fracture (HR, 0.64; 95% CI, 0.49-0.84; P = .0012).
The study’s predominantly male population is important because men also get osteoporosis and are frequently overlooked, according to Anne Schafer, MD, who was the lead author of the study. “Even after they fracture, men are sometimes less likely to get care to prevent the next fracture. We’ve shown here that especially men who are on the older side, who go through surgical weight loss, do have a higher risk of fracture compared to those who are similarly obese but have not had the operation,” said Dr. Schafer, a professor of medicine at the University of California, San Francisco, and chief of endocrinology and metabolism at the San Francisco VA Medical Center.
There are limited data on fracture risk after sleeve gastrectomy. “I think this is one of the first times that I’ve been able to demonstrate that there was a higher risk of fracture with sleeve gastrectomy in comparison with nonsurgical cohorts. Of course, it’s necessary to confirm these findings in further studies, but it’s interesting,” said Julien Paccou, MD, who attended the poster session and was asked for comment. His group’s study of a French population showed an increased fracture risk associated with RYGB but not sleeve gastrectomy. Another study found a reduction of fracture risk associated with sleeve gastrectomy and no difference between RYGB and nonsurgical matched control patients in a Medicare population.
In fact, there is a belief that fracture risk may be lower with sleeve gastrectomy, according to Dr. Schafer. “It’s part of why it’s so popular,” she said.
The reasons for increased fracture risk following surgical weight loss remains unknown, according to Dr. Paccou, but they could include mechanical unloading, loss of lean mass, and hormone and nutrition changes. “There are many, many factors,” said Dr. Paccou, a professor of rheumatology at Hospital Roger Salengro in Lille, France.
The study’s findings of increased risk of fracture after sleeve gastrectomy may be an argument against malabsorption because the procedure shouldn’t affect nutrient absorption. It suggests that other factors are at play. “It’s not the only reason,” Dr. Schafer said.
There are recommendations for postbariatric surgery care to optimize bone health, such as protein intake and calcium and vitamin D targets, along with lifestyle factors. “Despite all those [efforts], we still know that bone loss occurs,” Dr. Koh said. In fact, the group is conducting a study funded by Amgen of the use of denosumab (Prolia) for the prevention of high-turnover bone loss after RYGB and sleeve gastrectomy.
Dr. Schafer has received research support from Bone Health Technologies and Amgen. Dr. Koh and Dr. Paccou have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VANCOUVER – Patients who undergo either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy are at an increased risk of fracture, compared with patients with obesity who do not undergo surgery, according to a new analysis of a predominantly male group of U.S. veterans.
Previous studies involving premenopausal women have found a risk of bone mineral density loss and fracture with bariatric surgery, but little was known about the risk among men. Research has also shown an increase in risk after RYGB, but there is less information on risks associated with sleeve gastrectomy, though it is now the most common surgery for weight loss.
Bone density loss after bariatric surgery has been shown to be significant, according to Eileen H. Koh, MD. “It’s quite a lot of bone loss, quickly,” said Dr. Koh, a graduated fellow from the endocrinology program at the University of California, San Francisco, who is moving to the University of Washington, Seattle.
Those observations generally come from studies of younger women. The purpose of the new study “was to see if we see the same risk of fracture in veterans who are older men, so kind of the opposite of the typical bariatric patient,” said Dr. Koh, who presented the research at the annual meeting of the American Society for Bone and Mineral Research.
The researchers analyzed data from 8,299 U.S. veterans who underwent sleeve gastrectomy (41%), RYGB (51%), adjustable gastric banding (4%), or an unspecified bariatric procedure (4%) between 2000 and 2020. They were matched with 24,877 individuals with obesity who did not undergo surgery. The investigators excluded individuals who were at high risk of fracture because of another condition, such as organ transplantation or dialysis. Men made up 70% of both surgical and nonsurgical groups. The mean age was 52 years for both, and 89% and 88% were not Hispanic or Latino, respectively. The proportion of White individuals was 72% and 64%, and the proportion of Black individuals was 18% and 24%.
After adjustment for demographic variables and comorbidities, bariatric surgery was associated with a 68% increased risk of fracture (hazard ratio, 1.68; 95% confidence interval, 1.57-1.80), including hip fractures (HR, 2.42; 95% CI, 1.98-2.97), spine (HR, 1.82; 95% CI, 1.61-2.06), radius/ulna (HR, 2.38; 95% CI, 2.05-2.77), humerus (HR, 1.56; 95% CI, 1.28-1.89), pelvis (HR, 2.41; 95% CI, 1.68-3.46), and tibia/fibula/ankle (HR, 1.50; 95% CI, 1.33-1.69). Increased fracture risk was associated with RYGB (HR, 1.93; 95% CI, 1.75-2.12) and sleeve gastrectomy (HR, 1.50; 95% CI, 1.33-1.69) but not adjustable gastric banding.
Compared with sleeve gastrectomy, adjustable gastric banding was associated with a decreased risk of fracture (HR, 0.64; 95% CI, 0.49-0.84; P = .0012).
The study’s predominantly male population is important because men also get osteoporosis and are frequently overlooked, according to Anne Schafer, MD, who was the lead author of the study. “Even after they fracture, men are sometimes less likely to get care to prevent the next fracture. We’ve shown here that especially men who are on the older side, who go through surgical weight loss, do have a higher risk of fracture compared to those who are similarly obese but have not had the operation,” said Dr. Schafer, a professor of medicine at the University of California, San Francisco, and chief of endocrinology and metabolism at the San Francisco VA Medical Center.
There are limited data on fracture risk after sleeve gastrectomy. “I think this is one of the first times that I’ve been able to demonstrate that there was a higher risk of fracture with sleeve gastrectomy in comparison with nonsurgical cohorts. Of course, it’s necessary to confirm these findings in further studies, but it’s interesting,” said Julien Paccou, MD, who attended the poster session and was asked for comment. His group’s study of a French population showed an increased fracture risk associated with RYGB but not sleeve gastrectomy. Another study found a reduction of fracture risk associated with sleeve gastrectomy and no difference between RYGB and nonsurgical matched control patients in a Medicare population.
In fact, there is a belief that fracture risk may be lower with sleeve gastrectomy, according to Dr. Schafer. “It’s part of why it’s so popular,” she said.
The reasons for increased fracture risk following surgical weight loss remains unknown, according to Dr. Paccou, but they could include mechanical unloading, loss of lean mass, and hormone and nutrition changes. “There are many, many factors,” said Dr. Paccou, a professor of rheumatology at Hospital Roger Salengro in Lille, France.
The study’s findings of increased risk of fracture after sleeve gastrectomy may be an argument against malabsorption because the procedure shouldn’t affect nutrient absorption. It suggests that other factors are at play. “It’s not the only reason,” Dr. Schafer said.
There are recommendations for postbariatric surgery care to optimize bone health, such as protein intake and calcium and vitamin D targets, along with lifestyle factors. “Despite all those [efforts], we still know that bone loss occurs,” Dr. Koh said. In fact, the group is conducting a study funded by Amgen of the use of denosumab (Prolia) for the prevention of high-turnover bone loss after RYGB and sleeve gastrectomy.
Dr. Schafer has received research support from Bone Health Technologies and Amgen. Dr. Koh and Dr. Paccou have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VANCOUVER – Patients who undergo either Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy are at an increased risk of fracture, compared with patients with obesity who do not undergo surgery, according to a new analysis of a predominantly male group of U.S. veterans.
Previous studies involving premenopausal women have found a risk of bone mineral density loss and fracture with bariatric surgery, but little was known about the risk among men. Research has also shown an increase in risk after RYGB, but there is less information on risks associated with sleeve gastrectomy, though it is now the most common surgery for weight loss.
Bone density loss after bariatric surgery has been shown to be significant, according to Eileen H. Koh, MD. “It’s quite a lot of bone loss, quickly,” said Dr. Koh, a graduated fellow from the endocrinology program at the University of California, San Francisco, who is moving to the University of Washington, Seattle.
Those observations generally come from studies of younger women. The purpose of the new study “was to see if we see the same risk of fracture in veterans who are older men, so kind of the opposite of the typical bariatric patient,” said Dr. Koh, who presented the research at the annual meeting of the American Society for Bone and Mineral Research.
The researchers analyzed data from 8,299 U.S. veterans who underwent sleeve gastrectomy (41%), RYGB (51%), adjustable gastric banding (4%), or an unspecified bariatric procedure (4%) between 2000 and 2020. They were matched with 24,877 individuals with obesity who did not undergo surgery. The investigators excluded individuals who were at high risk of fracture because of another condition, such as organ transplantation or dialysis. Men made up 70% of both surgical and nonsurgical groups. The mean age was 52 years for both, and 89% and 88% were not Hispanic or Latino, respectively. The proportion of White individuals was 72% and 64%, and the proportion of Black individuals was 18% and 24%.
After adjustment for demographic variables and comorbidities, bariatric surgery was associated with a 68% increased risk of fracture (hazard ratio, 1.68; 95% confidence interval, 1.57-1.80), including hip fractures (HR, 2.42; 95% CI, 1.98-2.97), spine (HR, 1.82; 95% CI, 1.61-2.06), radius/ulna (HR, 2.38; 95% CI, 2.05-2.77), humerus (HR, 1.56; 95% CI, 1.28-1.89), pelvis (HR, 2.41; 95% CI, 1.68-3.46), and tibia/fibula/ankle (HR, 1.50; 95% CI, 1.33-1.69). Increased fracture risk was associated with RYGB (HR, 1.93; 95% CI, 1.75-2.12) and sleeve gastrectomy (HR, 1.50; 95% CI, 1.33-1.69) but not adjustable gastric banding.
Compared with sleeve gastrectomy, adjustable gastric banding was associated with a decreased risk of fracture (HR, 0.64; 95% CI, 0.49-0.84; P = .0012).
The study’s predominantly male population is important because men also get osteoporosis and are frequently overlooked, according to Anne Schafer, MD, who was the lead author of the study. “Even after they fracture, men are sometimes less likely to get care to prevent the next fracture. We’ve shown here that especially men who are on the older side, who go through surgical weight loss, do have a higher risk of fracture compared to those who are similarly obese but have not had the operation,” said Dr. Schafer, a professor of medicine at the University of California, San Francisco, and chief of endocrinology and metabolism at the San Francisco VA Medical Center.
There are limited data on fracture risk after sleeve gastrectomy. “I think this is one of the first times that I’ve been able to demonstrate that there was a higher risk of fracture with sleeve gastrectomy in comparison with nonsurgical cohorts. Of course, it’s necessary to confirm these findings in further studies, but it’s interesting,” said Julien Paccou, MD, who attended the poster session and was asked for comment. His group’s study of a French population showed an increased fracture risk associated with RYGB but not sleeve gastrectomy. Another study found a reduction of fracture risk associated with sleeve gastrectomy and no difference between RYGB and nonsurgical matched control patients in a Medicare population.
In fact, there is a belief that fracture risk may be lower with sleeve gastrectomy, according to Dr. Schafer. “It’s part of why it’s so popular,” she said.
The reasons for increased fracture risk following surgical weight loss remains unknown, according to Dr. Paccou, but they could include mechanical unloading, loss of lean mass, and hormone and nutrition changes. “There are many, many factors,” said Dr. Paccou, a professor of rheumatology at Hospital Roger Salengro in Lille, France.
The study’s findings of increased risk of fracture after sleeve gastrectomy may be an argument against malabsorption because the procedure shouldn’t affect nutrient absorption. It suggests that other factors are at play. “It’s not the only reason,” Dr. Schafer said.
There are recommendations for postbariatric surgery care to optimize bone health, such as protein intake and calcium and vitamin D targets, along with lifestyle factors. “Despite all those [efforts], we still know that bone loss occurs,” Dr. Koh said. In fact, the group is conducting a study funded by Amgen of the use of denosumab (Prolia) for the prevention of high-turnover bone loss after RYGB and sleeve gastrectomy.
Dr. Schafer has received research support from Bone Health Technologies and Amgen. Dr. Koh and Dr. Paccou have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ASBMR 2023
Tricyclics may raise fracture risk in type 2 diabetes
VANCOUVER – , independent of any prevalent neuropathy, according to findings from an analysis of a large, randomized clinical trial.
Although the findings are suggestive, they don’t definitively pin blame on TCAs, said Rachel Elam, MD, who presented the study at the annual meeting of the American Society for Bone and Mineral Research. “I think that there’s not enough information to conclude that tricyclic antidepressants directly lead to fractures, but I think it opens the door [to] something we should look into more. Is it being mediated by a better predictor, or is it the medication itself? I think it’s more hypothesis generating,” said Dr. Elam, an assistant professor of medicine in the division of rheumatology at the Medical College of Georgia, Augusta.
Patients with type 2 diabetes are known to be at increased risk of fracture, but prediction tools tend to underestimate this risk, Dr. Elam said. “Type 2 diabetes–specific clinical risk factors may be helpful for finding out fracture risk in this population,” Dr. Elam said during her talk.
Glycemic control is one candidate risk factor because advanced glycation end products are linked to reduced bone strength. Other factors include antidiabetic medication use, neuropathy, and microvascular disease, which has been linked to increased cortical porosity.
The study examined a somewhat younger population than previous surveys, having drawn from the Look AHEAD-C clinical trial, which examined the effects of an intensive lifestyle intervention on type 2 diabetes. Look AHEAD-C included 4,697 participants aged 45-75 from 16 U.S. clinical sites. Participants had a body mass index of 25.0 kg/m2 or higher and hemoglobin A1c levels of 11% or below.
Dr. Elam cited the database’s inclusion of factors like A1c levels, renal parameters, and diabetic neuropathy. “It gave us a really good population to look at those risk factors” in a large group of people with type 2 diabetes, she said.
Over a median follow-up of 16.6 years, there were 649 participants with incident first clinical fracture(s). Statistically significant factors predicting fracture risk included TCA use (hazard ratio, 2.24; 95% confidence interval, 1.14-4.43), female gender (HR, 2.20; 95% CI, 1.83-2.66), insulin use (HR, 1.26; 95% CI, 1.02-1.57), increases in A1c level (per 1% increase: HR, 1.12; 95% CI, 1.04-1.20), age (HR, 1.02; 95% CI, 1.01-1.04), other or mixed race/ethnicity (HR, 0.68; 95% CI, 0.52-0.87), Hispanic White race/ethnicity (HR, 0.60; 95% CI, 0.39-0.91), non-Hispanic Black race/ethnicity (HR, 0.35; 95% CI, 0.26-0.47), and estrogen use (HR, 0.65; 95% CI, 0.44-0.98).
During the Q&A session following the presentation, Elsa Strotmeyer, PhD, commented that TCAs have been linked to central nervous system pathways in falls in other populations. “It’s a very nice study. It’s important to look at the diabetes complications related to the fracture risk, but I thought that they should have emphasized some more of the diabetes complications being related to fracture rather than these tricyclic antidepressants, because that is not a unique factor to that population,” said Dr. Strotmeyer, who is an associate professor of epidemiology at the University of Pittsburgh.
Instead, she noted a different strength of the study. “The study population is important because they’re a relatively young population with type 2 diabetes, compared to many studies [that] have been published in older populations. Showing similar things that we found in older populations was the unique piece and the important piece of this study,” Dr. Strotmeyer said.
Ultimately, the model wasn’t sufficient to be used as a fall risk predictor, but it should inform future work, according to Dr. Elam. “I think it does lay some new groundwork that when we’re looking forward, it may [help in building] other models to better predict fracture risk in type 2 diabetes. Things that would be important to include [in future models] would be medication use, such as tricyclic antidepressants,” and to make sure we include glycemic control, A1c, and insulin medication.
The study was independently funded. Dr. Elam and Dr. Strotmeyer report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VANCOUVER – , independent of any prevalent neuropathy, according to findings from an analysis of a large, randomized clinical trial.
Although the findings are suggestive, they don’t definitively pin blame on TCAs, said Rachel Elam, MD, who presented the study at the annual meeting of the American Society for Bone and Mineral Research. “I think that there’s not enough information to conclude that tricyclic antidepressants directly lead to fractures, but I think it opens the door [to] something we should look into more. Is it being mediated by a better predictor, or is it the medication itself? I think it’s more hypothesis generating,” said Dr. Elam, an assistant professor of medicine in the division of rheumatology at the Medical College of Georgia, Augusta.
Patients with type 2 diabetes are known to be at increased risk of fracture, but prediction tools tend to underestimate this risk, Dr. Elam said. “Type 2 diabetes–specific clinical risk factors may be helpful for finding out fracture risk in this population,” Dr. Elam said during her talk.
Glycemic control is one candidate risk factor because advanced glycation end products are linked to reduced bone strength. Other factors include antidiabetic medication use, neuropathy, and microvascular disease, which has been linked to increased cortical porosity.
The study examined a somewhat younger population than previous surveys, having drawn from the Look AHEAD-C clinical trial, which examined the effects of an intensive lifestyle intervention on type 2 diabetes. Look AHEAD-C included 4,697 participants aged 45-75 from 16 U.S. clinical sites. Participants had a body mass index of 25.0 kg/m2 or higher and hemoglobin A1c levels of 11% or below.
Dr. Elam cited the database’s inclusion of factors like A1c levels, renal parameters, and diabetic neuropathy. “It gave us a really good population to look at those risk factors” in a large group of people with type 2 diabetes, she said.
Over a median follow-up of 16.6 years, there were 649 participants with incident first clinical fracture(s). Statistically significant factors predicting fracture risk included TCA use (hazard ratio, 2.24; 95% confidence interval, 1.14-4.43), female gender (HR, 2.20; 95% CI, 1.83-2.66), insulin use (HR, 1.26; 95% CI, 1.02-1.57), increases in A1c level (per 1% increase: HR, 1.12; 95% CI, 1.04-1.20), age (HR, 1.02; 95% CI, 1.01-1.04), other or mixed race/ethnicity (HR, 0.68; 95% CI, 0.52-0.87), Hispanic White race/ethnicity (HR, 0.60; 95% CI, 0.39-0.91), non-Hispanic Black race/ethnicity (HR, 0.35; 95% CI, 0.26-0.47), and estrogen use (HR, 0.65; 95% CI, 0.44-0.98).
During the Q&A session following the presentation, Elsa Strotmeyer, PhD, commented that TCAs have been linked to central nervous system pathways in falls in other populations. “It’s a very nice study. It’s important to look at the diabetes complications related to the fracture risk, but I thought that they should have emphasized some more of the diabetes complications being related to fracture rather than these tricyclic antidepressants, because that is not a unique factor to that population,” said Dr. Strotmeyer, who is an associate professor of epidemiology at the University of Pittsburgh.
Instead, she noted a different strength of the study. “The study population is important because they’re a relatively young population with type 2 diabetes, compared to many studies [that] have been published in older populations. Showing similar things that we found in older populations was the unique piece and the important piece of this study,” Dr. Strotmeyer said.
Ultimately, the model wasn’t sufficient to be used as a fall risk predictor, but it should inform future work, according to Dr. Elam. “I think it does lay some new groundwork that when we’re looking forward, it may [help in building] other models to better predict fracture risk in type 2 diabetes. Things that would be important to include [in future models] would be medication use, such as tricyclic antidepressants,” and to make sure we include glycemic control, A1c, and insulin medication.
The study was independently funded. Dr. Elam and Dr. Strotmeyer report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VANCOUVER – , independent of any prevalent neuropathy, according to findings from an analysis of a large, randomized clinical trial.
Although the findings are suggestive, they don’t definitively pin blame on TCAs, said Rachel Elam, MD, who presented the study at the annual meeting of the American Society for Bone and Mineral Research. “I think that there’s not enough information to conclude that tricyclic antidepressants directly lead to fractures, but I think it opens the door [to] something we should look into more. Is it being mediated by a better predictor, or is it the medication itself? I think it’s more hypothesis generating,” said Dr. Elam, an assistant professor of medicine in the division of rheumatology at the Medical College of Georgia, Augusta.
Patients with type 2 diabetes are known to be at increased risk of fracture, but prediction tools tend to underestimate this risk, Dr. Elam said. “Type 2 diabetes–specific clinical risk factors may be helpful for finding out fracture risk in this population,” Dr. Elam said during her talk.
Glycemic control is one candidate risk factor because advanced glycation end products are linked to reduced bone strength. Other factors include antidiabetic medication use, neuropathy, and microvascular disease, which has been linked to increased cortical porosity.
The study examined a somewhat younger population than previous surveys, having drawn from the Look AHEAD-C clinical trial, which examined the effects of an intensive lifestyle intervention on type 2 diabetes. Look AHEAD-C included 4,697 participants aged 45-75 from 16 U.S. clinical sites. Participants had a body mass index of 25.0 kg/m2 or higher and hemoglobin A1c levels of 11% or below.
Dr. Elam cited the database’s inclusion of factors like A1c levels, renal parameters, and diabetic neuropathy. “It gave us a really good population to look at those risk factors” in a large group of people with type 2 diabetes, she said.
Over a median follow-up of 16.6 years, there were 649 participants with incident first clinical fracture(s). Statistically significant factors predicting fracture risk included TCA use (hazard ratio, 2.24; 95% confidence interval, 1.14-4.43), female gender (HR, 2.20; 95% CI, 1.83-2.66), insulin use (HR, 1.26; 95% CI, 1.02-1.57), increases in A1c level (per 1% increase: HR, 1.12; 95% CI, 1.04-1.20), age (HR, 1.02; 95% CI, 1.01-1.04), other or mixed race/ethnicity (HR, 0.68; 95% CI, 0.52-0.87), Hispanic White race/ethnicity (HR, 0.60; 95% CI, 0.39-0.91), non-Hispanic Black race/ethnicity (HR, 0.35; 95% CI, 0.26-0.47), and estrogen use (HR, 0.65; 95% CI, 0.44-0.98).
During the Q&A session following the presentation, Elsa Strotmeyer, PhD, commented that TCAs have been linked to central nervous system pathways in falls in other populations. “It’s a very nice study. It’s important to look at the diabetes complications related to the fracture risk, but I thought that they should have emphasized some more of the diabetes complications being related to fracture rather than these tricyclic antidepressants, because that is not a unique factor to that population,” said Dr. Strotmeyer, who is an associate professor of epidemiology at the University of Pittsburgh.
Instead, she noted a different strength of the study. “The study population is important because they’re a relatively young population with type 2 diabetes, compared to many studies [that] have been published in older populations. Showing similar things that we found in older populations was the unique piece and the important piece of this study,” Dr. Strotmeyer said.
Ultimately, the model wasn’t sufficient to be used as a fall risk predictor, but it should inform future work, according to Dr. Elam. “I think it does lay some new groundwork that when we’re looking forward, it may [help in building] other models to better predict fracture risk in type 2 diabetes. Things that would be important to include [in future models] would be medication use, such as tricyclic antidepressants,” and to make sure we include glycemic control, A1c, and insulin medication.
The study was independently funded. Dr. Elam and Dr. Strotmeyer report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ASBMR 2023
In ILD, ECMO linked to good outcomes as bridge to transplant
Extracorporeal membrane oxygen support appears to be beneficial in patients with advanced interstitial lung disease (ILD), according to a new meta-analysis. Specifically,
, although the confidence in the finding was low.ECMO has been used increasingly in ILD patients over the past 10-15 years for acute decompensation as well as a bridge to lung transplant, according to Prasanth Balasubramanian, MD, but clinical evidence for its use is limited to case series or short-term retrospective studies. “We don’t have robust evidence on whether it really helps with the outcome, and which mode is better, so that’s why we decided to do a study on this,” said Dr. Balasubramanian, who is a fellow in pulmonary critical care at Mayo Clinic (Jacksonville, Fla.). He presented the new research at the annual meeting of the American College of Chest Physicians (CHEST).
The results were encouraging, according to the study’s lead author Pramod Guru, MD. “I think what we take from this analysis is that ECMO should not be considered as a contraindication for people you are considering for lung transplant. If we have this population of people who are very sick, but we have the opportunity to solve them with VA ECMO and then give the transplantation possibly, that may be the way,” said Dr. Guru, who is a critical care specialist at Mayo Clinic, Jacksonville, Fla. He acknowledged that more work needs to be done to determine whether VA or VV is best in specific patient populations.
The meta-analysis included 18 studies with a total of 1,341 patients, who were a mean age of 55.89 years and 61.08% of whom were male. Most procedures (75.3%) were VV. The overall mortality was 52.6%, including 59.7% for VV ECMO and 34.2% for VA ECMO. The survival difference did not reach statistical significance (odds ratio, 0.48; P = .11). There was also no significant difference in survival between patients who underwent ECMO and those who did not undergo ECMO (OR, 0.48; P = .43).
The researchers also analyzed 13 studies with 1,002 patients that looked at ECMO as a bridge to transplant (mean age, 52.1; 52.2% male; 49.3% VV, 31.1% VA, 32.4% cardiopulmonary bypass). Mortality was lower in the VA group than in the VV group (odds ratio, 0.62; P = .04).
“VA ECMO is generally for sicker patients, so it’s odd that the patients who are on the more aggressive support had lower mortality. But it’s good, it says it works,” said Chris Carroll, MD, an intensivist at the University of Florida, Jacksonville, who was asked to comment on the study.
The finding may also be an artifact of bias in the retrospective data, according to Joshua Diamond, MD, who comoderated the session where the study was presented. He noted age, physical function, and illness severity, among other factors can play a role in decision-making. “I have a feeling that what you’re seeing is a very carefully selected patient population as opposed to a true mortality benefit with VA versus VV ECMO,” said Dr. Diamond, who is associate medical director of the Penn Lung Transplant Program in Philadelphia.
Another weakness of the study is that ECMO techniques and devices have changed over time, making some of the older data less relevant to current practice. Overall Dr. Diamond described the study as interesting, but “I’d like to see a bit more granularity of data to figure out who makes or doesn’t make a good candidate,” said Dr. Diamond.
Patients with ILD undergoing ECMO as a bridge to transplant had a higher 1-year posttransplant mortality than patients with other causes for transplant (OR, 1.78; P<.01). However, this finding relied on two retrospective studies using the UNOS database at different time points (2001-2012 and 2015-2020), leading to potential confounders and risk of bias.
Dr. Balasubramanian recognized the limitations of the analysis. “We do think that further prospective studies comparing various modalities would be essential, although it would be challenging,” he said.
Nevertheless, Dr. Guru said that his own center is changing its patient selection criteria for ECMO and will begin to collect prospective data: “I would say that in 12 months we’ll have our own data to support what we are doing.”
The study can also inform patients and family who are trying to make a potential end-of-life decision about pursuing aggressive ECMO therapy. “This study says that if you choose to pursue that more aggressive therapy, you may still have a good outcome. A patient might say, ‘Why am I going to go through all this? Is it just prolonging my death, or is there a chance of saving my life? I think what this study shows is that it does have potential of saving their life,” said Dr. Carroll.
Dr. Balasubramanian, Dr. Guru, and Dr. Carroll have no relevant financial disclosures.
Extracorporeal membrane oxygen support appears to be beneficial in patients with advanced interstitial lung disease (ILD), according to a new meta-analysis. Specifically,
, although the confidence in the finding was low.ECMO has been used increasingly in ILD patients over the past 10-15 years for acute decompensation as well as a bridge to lung transplant, according to Prasanth Balasubramanian, MD, but clinical evidence for its use is limited to case series or short-term retrospective studies. “We don’t have robust evidence on whether it really helps with the outcome, and which mode is better, so that’s why we decided to do a study on this,” said Dr. Balasubramanian, who is a fellow in pulmonary critical care at Mayo Clinic (Jacksonville, Fla.). He presented the new research at the annual meeting of the American College of Chest Physicians (CHEST).
The results were encouraging, according to the study’s lead author Pramod Guru, MD. “I think what we take from this analysis is that ECMO should not be considered as a contraindication for people you are considering for lung transplant. If we have this population of people who are very sick, but we have the opportunity to solve them with VA ECMO and then give the transplantation possibly, that may be the way,” said Dr. Guru, who is a critical care specialist at Mayo Clinic, Jacksonville, Fla. He acknowledged that more work needs to be done to determine whether VA or VV is best in specific patient populations.
The meta-analysis included 18 studies with a total of 1,341 patients, who were a mean age of 55.89 years and 61.08% of whom were male. Most procedures (75.3%) were VV. The overall mortality was 52.6%, including 59.7% for VV ECMO and 34.2% for VA ECMO. The survival difference did not reach statistical significance (odds ratio, 0.48; P = .11). There was also no significant difference in survival between patients who underwent ECMO and those who did not undergo ECMO (OR, 0.48; P = .43).
The researchers also analyzed 13 studies with 1,002 patients that looked at ECMO as a bridge to transplant (mean age, 52.1; 52.2% male; 49.3% VV, 31.1% VA, 32.4% cardiopulmonary bypass). Mortality was lower in the VA group than in the VV group (odds ratio, 0.62; P = .04).
“VA ECMO is generally for sicker patients, so it’s odd that the patients who are on the more aggressive support had lower mortality. But it’s good, it says it works,” said Chris Carroll, MD, an intensivist at the University of Florida, Jacksonville, who was asked to comment on the study.
The finding may also be an artifact of bias in the retrospective data, according to Joshua Diamond, MD, who comoderated the session where the study was presented. He noted age, physical function, and illness severity, among other factors can play a role in decision-making. “I have a feeling that what you’re seeing is a very carefully selected patient population as opposed to a true mortality benefit with VA versus VV ECMO,” said Dr. Diamond, who is associate medical director of the Penn Lung Transplant Program in Philadelphia.
Another weakness of the study is that ECMO techniques and devices have changed over time, making some of the older data less relevant to current practice. Overall Dr. Diamond described the study as interesting, but “I’d like to see a bit more granularity of data to figure out who makes or doesn’t make a good candidate,” said Dr. Diamond.
Patients with ILD undergoing ECMO as a bridge to transplant had a higher 1-year posttransplant mortality than patients with other causes for transplant (OR, 1.78; P<.01). However, this finding relied on two retrospective studies using the UNOS database at different time points (2001-2012 and 2015-2020), leading to potential confounders and risk of bias.
Dr. Balasubramanian recognized the limitations of the analysis. “We do think that further prospective studies comparing various modalities would be essential, although it would be challenging,” he said.
Nevertheless, Dr. Guru said that his own center is changing its patient selection criteria for ECMO and will begin to collect prospective data: “I would say that in 12 months we’ll have our own data to support what we are doing.”
The study can also inform patients and family who are trying to make a potential end-of-life decision about pursuing aggressive ECMO therapy. “This study says that if you choose to pursue that more aggressive therapy, you may still have a good outcome. A patient might say, ‘Why am I going to go through all this? Is it just prolonging my death, or is there a chance of saving my life? I think what this study shows is that it does have potential of saving their life,” said Dr. Carroll.
Dr. Balasubramanian, Dr. Guru, and Dr. Carroll have no relevant financial disclosures.
Extracorporeal membrane oxygen support appears to be beneficial in patients with advanced interstitial lung disease (ILD), according to a new meta-analysis. Specifically,
, although the confidence in the finding was low.ECMO has been used increasingly in ILD patients over the past 10-15 years for acute decompensation as well as a bridge to lung transplant, according to Prasanth Balasubramanian, MD, but clinical evidence for its use is limited to case series or short-term retrospective studies. “We don’t have robust evidence on whether it really helps with the outcome, and which mode is better, so that’s why we decided to do a study on this,” said Dr. Balasubramanian, who is a fellow in pulmonary critical care at Mayo Clinic (Jacksonville, Fla.). He presented the new research at the annual meeting of the American College of Chest Physicians (CHEST).
The results were encouraging, according to the study’s lead author Pramod Guru, MD. “I think what we take from this analysis is that ECMO should not be considered as a contraindication for people you are considering for lung transplant. If we have this population of people who are very sick, but we have the opportunity to solve them with VA ECMO and then give the transplantation possibly, that may be the way,” said Dr. Guru, who is a critical care specialist at Mayo Clinic, Jacksonville, Fla. He acknowledged that more work needs to be done to determine whether VA or VV is best in specific patient populations.
The meta-analysis included 18 studies with a total of 1,341 patients, who were a mean age of 55.89 years and 61.08% of whom were male. Most procedures (75.3%) were VV. The overall mortality was 52.6%, including 59.7% for VV ECMO and 34.2% for VA ECMO. The survival difference did not reach statistical significance (odds ratio, 0.48; P = .11). There was also no significant difference in survival between patients who underwent ECMO and those who did not undergo ECMO (OR, 0.48; P = .43).
The researchers also analyzed 13 studies with 1,002 patients that looked at ECMO as a bridge to transplant (mean age, 52.1; 52.2% male; 49.3% VV, 31.1% VA, 32.4% cardiopulmonary bypass). Mortality was lower in the VA group than in the VV group (odds ratio, 0.62; P = .04).
“VA ECMO is generally for sicker patients, so it’s odd that the patients who are on the more aggressive support had lower mortality. But it’s good, it says it works,” said Chris Carroll, MD, an intensivist at the University of Florida, Jacksonville, who was asked to comment on the study.
The finding may also be an artifact of bias in the retrospective data, according to Joshua Diamond, MD, who comoderated the session where the study was presented. He noted age, physical function, and illness severity, among other factors can play a role in decision-making. “I have a feeling that what you’re seeing is a very carefully selected patient population as opposed to a true mortality benefit with VA versus VV ECMO,” said Dr. Diamond, who is associate medical director of the Penn Lung Transplant Program in Philadelphia.
Another weakness of the study is that ECMO techniques and devices have changed over time, making some of the older data less relevant to current practice. Overall Dr. Diamond described the study as interesting, but “I’d like to see a bit more granularity of data to figure out who makes or doesn’t make a good candidate,” said Dr. Diamond.
Patients with ILD undergoing ECMO as a bridge to transplant had a higher 1-year posttransplant mortality than patients with other causes for transplant (OR, 1.78; P<.01). However, this finding relied on two retrospective studies using the UNOS database at different time points (2001-2012 and 2015-2020), leading to potential confounders and risk of bias.
Dr. Balasubramanian recognized the limitations of the analysis. “We do think that further prospective studies comparing various modalities would be essential, although it would be challenging,” he said.
Nevertheless, Dr. Guru said that his own center is changing its patient selection criteria for ECMO and will begin to collect prospective data: “I would say that in 12 months we’ll have our own data to support what we are doing.”
The study can also inform patients and family who are trying to make a potential end-of-life decision about pursuing aggressive ECMO therapy. “This study says that if you choose to pursue that more aggressive therapy, you may still have a good outcome. A patient might say, ‘Why am I going to go through all this? Is it just prolonging my death, or is there a chance of saving my life? I think what this study shows is that it does have potential of saving their life,” said Dr. Carroll.
Dr. Balasubramanian, Dr. Guru, and Dr. Carroll have no relevant financial disclosures.
FROM CHEST 2023
New calculator tool estimates fracture risk on dialysis
VANCOUVER – A new calculator that predicts short-term fracture risk at both 1 year and 3 years in patients on dialysis performed well in a study presented at the annual meeting of the American Society for Bone and Mineral Research.
The tool will soon be available on QxMD Calculate, which provides free decision-support tools for physicians, said presenter Andrea Cowan, MD, an assistant professor of medicine at the University of Western Ontario, London.
Dialysis patients have an approximately fivefold increased risk for fracture, Dr. Cowan noted, compared with the general population. However, treatments to prevent fracture risk are relatively limited and can have significant side effects. Therefore, “you really want to make sure that the person you’re targeting for treatment is actually going to be at a reasonable risk of fracture,” she said.
The Fracture Risk Assessment Tool (FRAX) is useful, but it estimates 10-year fracture risk, which is too long of a time frame to be useful for dialysis patients who experience a 50% 5-year mortality, according to Dr. Cowan. It does not take kidney failure or severe hyperparathyroidism into account, and it also requires information like bone mineral density, which poses an additional burden for a dialysis patient already undergoing multiple tests.
The new calculator could also be useful for research because it doesn’t rely on clinical data that might not be generally available, such as parental fracture, smoking status, or body mass index. “There’s a move towards things like pragmatic trials, which use more routinely collected data, have broader inclusion criteria, and are often more cost efficient to run. This calculator should be relatively easy to implement in trials using routinely collected data to perhaps define a subgroup of patients who may be at high risk of fracture without having to apply really cumbersome tools,” Dr. Cowan said.
The researchers included 11,599 patients between ages 40 and 89 years who were treated at a single center in Ontario between 2010 and 2017. The mean age was 66.18 years, 38.6% were women, 64.1% had diabetes, 11.9% had liver disease, and median time on dialysis was 0.81 years. The patients’ median parathyroid hormone level was 30 pmol/L.
At 3 years, the cumulative incidence of any fracture was 7.36% (95% confidence interval, 6.89-7.85), including 2.62% for hip fracture (95% CI, 2.34-2.93), 1.36% for spine fracture (95% CI, 1.16-1.59), 1.93% for wrist or forearm (95% CI, 1.69-2.20), and 2.15% for the pelvis (95% CI, 1.89-2.43). The incidence for all fractures at 1 year was 2.93 (95% CI, 2.62-3.26).
Variables associated with fracture risk included female sex (hazard ratio, 1.46; 95% CI, 1.27-1.67), a previous fracture more than 1 year in the past (HR, 1.65; 95% CI, 1.37-2.00), a fracture in the past year (HR, 3.63; 95% CI, 2.86-4.60), and proton pump inhibitor use (HR, 1.23; 95% CI, 1.04-1.45). After inclusion of vitamin D use, steroid use, time on dialysis, calcium levels, phosphate levels, presence of diabetes, rheumatoid arthritis, and chronic liver disease, the full model had an area under the curve of 77.7 at 1 year (95% CI, 73.3-84.4) and 69.9 at 3 years (95% CI, 68.0-72.2). For hip fracture, the model had an AUC of 80.1 at 1 year (95% CI, 77.0-83.5) and 71.9 at 3 years (95% CI, 70.1-74.2).
During the Q&A session, Dr. Cowan was asked how the tool could be implemented clinically. She said that it could have value in discussing fracture prediction and prevention with patients, but it could also increase fracture risk awareness among nephrologists. “I need to convince a lot of my colleagues because they’re focused on other things, so having this [calculator] I think is both good from a patient as well as a practitioner perspective. And the treatments that we have in people with end-stage renal disease are limited, so you want to know that you’re really targeting the high-risk person before you potentially put them on denosumab and increase the risk of severe hypercalcemia and things like that,” Dr. Cowan said.
The study points out the challenges of predicting fracture risk for specific populations, according to session comoderator Evelyn Hsieh, MD. She noted that the study needs follow-up. “I don’t think they had gotten to a validation [in a separate cohort] yet,” said Dr. Hsieh, an associate professor of medicine (rheumatology) and epidemiology (chronic diseases) at Yale University, New Haven, Conn.
Dr. Cowan and Dr. Hsieh have no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
VANCOUVER – A new calculator that predicts short-term fracture risk at both 1 year and 3 years in patients on dialysis performed well in a study presented at the annual meeting of the American Society for Bone and Mineral Research.
The tool will soon be available on QxMD Calculate, which provides free decision-support tools for physicians, said presenter Andrea Cowan, MD, an assistant professor of medicine at the University of Western Ontario, London.
Dialysis patients have an approximately fivefold increased risk for fracture, Dr. Cowan noted, compared with the general population. However, treatments to prevent fracture risk are relatively limited and can have significant side effects. Therefore, “you really want to make sure that the person you’re targeting for treatment is actually going to be at a reasonable risk of fracture,” she said.
The Fracture Risk Assessment Tool (FRAX) is useful, but it estimates 10-year fracture risk, which is too long of a time frame to be useful for dialysis patients who experience a 50% 5-year mortality, according to Dr. Cowan. It does not take kidney failure or severe hyperparathyroidism into account, and it also requires information like bone mineral density, which poses an additional burden for a dialysis patient already undergoing multiple tests.
The new calculator could also be useful for research because it doesn’t rely on clinical data that might not be generally available, such as parental fracture, smoking status, or body mass index. “There’s a move towards things like pragmatic trials, which use more routinely collected data, have broader inclusion criteria, and are often more cost efficient to run. This calculator should be relatively easy to implement in trials using routinely collected data to perhaps define a subgroup of patients who may be at high risk of fracture without having to apply really cumbersome tools,” Dr. Cowan said.
The researchers included 11,599 patients between ages 40 and 89 years who were treated at a single center in Ontario between 2010 and 2017. The mean age was 66.18 years, 38.6% were women, 64.1% had diabetes, 11.9% had liver disease, and median time on dialysis was 0.81 years. The patients’ median parathyroid hormone level was 30 pmol/L.
At 3 years, the cumulative incidence of any fracture was 7.36% (95% confidence interval, 6.89-7.85), including 2.62% for hip fracture (95% CI, 2.34-2.93), 1.36% for spine fracture (95% CI, 1.16-1.59), 1.93% for wrist or forearm (95% CI, 1.69-2.20), and 2.15% for the pelvis (95% CI, 1.89-2.43). The incidence for all fractures at 1 year was 2.93 (95% CI, 2.62-3.26).
Variables associated with fracture risk included female sex (hazard ratio, 1.46; 95% CI, 1.27-1.67), a previous fracture more than 1 year in the past (HR, 1.65; 95% CI, 1.37-2.00), a fracture in the past year (HR, 3.63; 95% CI, 2.86-4.60), and proton pump inhibitor use (HR, 1.23; 95% CI, 1.04-1.45). After inclusion of vitamin D use, steroid use, time on dialysis, calcium levels, phosphate levels, presence of diabetes, rheumatoid arthritis, and chronic liver disease, the full model had an area under the curve of 77.7 at 1 year (95% CI, 73.3-84.4) and 69.9 at 3 years (95% CI, 68.0-72.2). For hip fracture, the model had an AUC of 80.1 at 1 year (95% CI, 77.0-83.5) and 71.9 at 3 years (95% CI, 70.1-74.2).
During the Q&A session, Dr. Cowan was asked how the tool could be implemented clinically. She said that it could have value in discussing fracture prediction and prevention with patients, but it could also increase fracture risk awareness among nephrologists. “I need to convince a lot of my colleagues because they’re focused on other things, so having this [calculator] I think is both good from a patient as well as a practitioner perspective. And the treatments that we have in people with end-stage renal disease are limited, so you want to know that you’re really targeting the high-risk person before you potentially put them on denosumab and increase the risk of severe hypercalcemia and things like that,” Dr. Cowan said.
The study points out the challenges of predicting fracture risk for specific populations, according to session comoderator Evelyn Hsieh, MD. She noted that the study needs follow-up. “I don’t think they had gotten to a validation [in a separate cohort] yet,” said Dr. Hsieh, an associate professor of medicine (rheumatology) and epidemiology (chronic diseases) at Yale University, New Haven, Conn.
Dr. Cowan and Dr. Hsieh have no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
VANCOUVER – A new calculator that predicts short-term fracture risk at both 1 year and 3 years in patients on dialysis performed well in a study presented at the annual meeting of the American Society for Bone and Mineral Research.
The tool will soon be available on QxMD Calculate, which provides free decision-support tools for physicians, said presenter Andrea Cowan, MD, an assistant professor of medicine at the University of Western Ontario, London.
Dialysis patients have an approximately fivefold increased risk for fracture, Dr. Cowan noted, compared with the general population. However, treatments to prevent fracture risk are relatively limited and can have significant side effects. Therefore, “you really want to make sure that the person you’re targeting for treatment is actually going to be at a reasonable risk of fracture,” she said.
The Fracture Risk Assessment Tool (FRAX) is useful, but it estimates 10-year fracture risk, which is too long of a time frame to be useful for dialysis patients who experience a 50% 5-year mortality, according to Dr. Cowan. It does not take kidney failure or severe hyperparathyroidism into account, and it also requires information like bone mineral density, which poses an additional burden for a dialysis patient already undergoing multiple tests.
The new calculator could also be useful for research because it doesn’t rely on clinical data that might not be generally available, such as parental fracture, smoking status, or body mass index. “There’s a move towards things like pragmatic trials, which use more routinely collected data, have broader inclusion criteria, and are often more cost efficient to run. This calculator should be relatively easy to implement in trials using routinely collected data to perhaps define a subgroup of patients who may be at high risk of fracture without having to apply really cumbersome tools,” Dr. Cowan said.
The researchers included 11,599 patients between ages 40 and 89 years who were treated at a single center in Ontario between 2010 and 2017. The mean age was 66.18 years, 38.6% were women, 64.1% had diabetes, 11.9% had liver disease, and median time on dialysis was 0.81 years. The patients’ median parathyroid hormone level was 30 pmol/L.
At 3 years, the cumulative incidence of any fracture was 7.36% (95% confidence interval, 6.89-7.85), including 2.62% for hip fracture (95% CI, 2.34-2.93), 1.36% for spine fracture (95% CI, 1.16-1.59), 1.93% for wrist or forearm (95% CI, 1.69-2.20), and 2.15% for the pelvis (95% CI, 1.89-2.43). The incidence for all fractures at 1 year was 2.93 (95% CI, 2.62-3.26).
Variables associated with fracture risk included female sex (hazard ratio, 1.46; 95% CI, 1.27-1.67), a previous fracture more than 1 year in the past (HR, 1.65; 95% CI, 1.37-2.00), a fracture in the past year (HR, 3.63; 95% CI, 2.86-4.60), and proton pump inhibitor use (HR, 1.23; 95% CI, 1.04-1.45). After inclusion of vitamin D use, steroid use, time on dialysis, calcium levels, phosphate levels, presence of diabetes, rheumatoid arthritis, and chronic liver disease, the full model had an area under the curve of 77.7 at 1 year (95% CI, 73.3-84.4) and 69.9 at 3 years (95% CI, 68.0-72.2). For hip fracture, the model had an AUC of 80.1 at 1 year (95% CI, 77.0-83.5) and 71.9 at 3 years (95% CI, 70.1-74.2).
During the Q&A session, Dr. Cowan was asked how the tool could be implemented clinically. She said that it could have value in discussing fracture prediction and prevention with patients, but it could also increase fracture risk awareness among nephrologists. “I need to convince a lot of my colleagues because they’re focused on other things, so having this [calculator] I think is both good from a patient as well as a practitioner perspective. And the treatments that we have in people with end-stage renal disease are limited, so you want to know that you’re really targeting the high-risk person before you potentially put them on denosumab and increase the risk of severe hypercalcemia and things like that,” Dr. Cowan said.
The study points out the challenges of predicting fracture risk for specific populations, according to session comoderator Evelyn Hsieh, MD. She noted that the study needs follow-up. “I don’t think they had gotten to a validation [in a separate cohort] yet,” said Dr. Hsieh, an associate professor of medicine (rheumatology) and epidemiology (chronic diseases) at Yale University, New Haven, Conn.
Dr. Cowan and Dr. Hsieh have no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
AT ASBMR 2023
Asthma with EoE linked to earlier hospitalization
, according to a new analysis of data from HCA Healthcare.
Not much work has been done on the overlap between the two conditions, both of which are believed to be driven by the action of both eosinophils and helper T cells, according to Linda Pham, DO, who presented the research at the annual meeting of the American College of Chest Physicians (CHEST).
“I have a colleague who is interested in GI and he’s really interested in EOE. We thought it would be nice to look at those populations of patients to see if there’s a correlation between them aside from just the atopic disease,” said Dr. Pham, who is an internal medicine resident at Riverside (Calif.) Community Hospital.
The findings underscore the need for assessing individual patient risk. “Having another concomitant disease like EoE, or maybe like atopic dermatitis, might cause you to have more severe [asthma] exacerbations causing you to go into the hospital more. I think if patients have more of these diseases, doctors can be more cognizant that they need to really be on top of treatment and make sure that [their patients] are aware of themselves so that if their symptoms exacerbate, they can go to the hospital and seek care,” said Dr. Pham.
The study was a retrospective analysis of 3,678,812 patients with asthma and 5,823 patients with both EoE and asthma. The data was drawn from 185 HCA hospitals, with records between 2016 and 2021.
The incidence of both asthma and asthma with EoE remained stable between 2016 and 2021. Dr. Pham pointed out that there are good methods to diagnose both conditions, which suggests that existing treatments are effective enough to be limiting the need for emergency treatment, according to Dr. Pham.
Among patients hospitalized with asthma alone, 72.55% were female, while 27.45% were male (P < .001). The numbers were much more evenly split among those with asthma and EoE, at 51.78% and 48.22%, respectively. The differing gender statistics aren’t easy to explain. “It’s not quite clear whether it’s because they just have more severe symptoms, or if it is other factors causing women to seek care more than their male counterparts. It could be personal biases, or it could be the asthma itself that is more severe in women,” said Dr. Pham.
When they broke down the analysis by sex, the researchers found that male EoE patients without asthma were a mean value of 5.517 years older than male EoE patients with asthma, and the mean difference was 5.480 years in female patients (P < .001 for both).
Although the direct cause of earlier hospitalization among patients with concomitant EoE and asthma is unclear, Dr. Pham speculated that the combination of atopic diseases may be leading to a stronger inflammatory response.
It remains to be seen if a similar relationship occurs with other atopic diseases, and future research could examine other factors. “I think it’d be good to look at not just age and gender, but BMI and occupation, things like that,” said Dr. Pham.
The study was of particular interest to Michelle Robertson, MD, who was in the audience. She is the director for clinical services at the Airborne Hazards and Burn Pits Center of Excellence at the New Jersey War-Related Illness and Injury Study Center. “We see a significant number of [veterans] who have been diagnosed with both asthma and eosinophilic esophagitis, and our thinking is that that is likely related to some of the military exposures: In particular, [what the] deployed veterans encountered in the Gulf War, [such as] the smoke from burn pits, sand and dust storms, and smoke from oil well fires. Our thinking is that the particulate matter, the PM 2.5, the very, very tiny particles, may be either sensitizing the lung area and/or esophagus and predisposing them to having those symptoms when they return home,” said Dr. Robertson, in an interview.
Particles in this size range may be able to bypass the protected areas of the nose and the lungs to reach the alveoli, where they could potentially interfere with the transfer of air between the lungs and the rest of the body, which could in turn lead to a variety of inflammatory conditions, according to Dr. Robertson.
She noted that particle exposure varies with a soldier’s wartime occupation, with higher exposures among mechanics and burn pit managers, for example. However, the highest levels of exposure do not predict later illness, which is a natural prompt for future research. “The second part of this whole pathophysiology is susceptibility. Is there something about those people that do get sick that makes them more susceptible than folks that don’t, even though they both have the same jobs?”
Dr. Pham and Dr. Robertson have no relevant financial disclosures.
, according to a new analysis of data from HCA Healthcare.
Not much work has been done on the overlap between the two conditions, both of which are believed to be driven by the action of both eosinophils and helper T cells, according to Linda Pham, DO, who presented the research at the annual meeting of the American College of Chest Physicians (CHEST).
“I have a colleague who is interested in GI and he’s really interested in EOE. We thought it would be nice to look at those populations of patients to see if there’s a correlation between them aside from just the atopic disease,” said Dr. Pham, who is an internal medicine resident at Riverside (Calif.) Community Hospital.
The findings underscore the need for assessing individual patient risk. “Having another concomitant disease like EoE, or maybe like atopic dermatitis, might cause you to have more severe [asthma] exacerbations causing you to go into the hospital more. I think if patients have more of these diseases, doctors can be more cognizant that they need to really be on top of treatment and make sure that [their patients] are aware of themselves so that if their symptoms exacerbate, they can go to the hospital and seek care,” said Dr. Pham.
The study was a retrospective analysis of 3,678,812 patients with asthma and 5,823 patients with both EoE and asthma. The data was drawn from 185 HCA hospitals, with records between 2016 and 2021.
The incidence of both asthma and asthma with EoE remained stable between 2016 and 2021. Dr. Pham pointed out that there are good methods to diagnose both conditions, which suggests that existing treatments are effective enough to be limiting the need for emergency treatment, according to Dr. Pham.
Among patients hospitalized with asthma alone, 72.55% were female, while 27.45% were male (P < .001). The numbers were much more evenly split among those with asthma and EoE, at 51.78% and 48.22%, respectively. The differing gender statistics aren’t easy to explain. “It’s not quite clear whether it’s because they just have more severe symptoms, or if it is other factors causing women to seek care more than their male counterparts. It could be personal biases, or it could be the asthma itself that is more severe in women,” said Dr. Pham.
When they broke down the analysis by sex, the researchers found that male EoE patients without asthma were a mean value of 5.517 years older than male EoE patients with asthma, and the mean difference was 5.480 years in female patients (P < .001 for both).
Although the direct cause of earlier hospitalization among patients with concomitant EoE and asthma is unclear, Dr. Pham speculated that the combination of atopic diseases may be leading to a stronger inflammatory response.
It remains to be seen if a similar relationship occurs with other atopic diseases, and future research could examine other factors. “I think it’d be good to look at not just age and gender, but BMI and occupation, things like that,” said Dr. Pham.
The study was of particular interest to Michelle Robertson, MD, who was in the audience. She is the director for clinical services at the Airborne Hazards and Burn Pits Center of Excellence at the New Jersey War-Related Illness and Injury Study Center. “We see a significant number of [veterans] who have been diagnosed with both asthma and eosinophilic esophagitis, and our thinking is that that is likely related to some of the military exposures: In particular, [what the] deployed veterans encountered in the Gulf War, [such as] the smoke from burn pits, sand and dust storms, and smoke from oil well fires. Our thinking is that the particulate matter, the PM 2.5, the very, very tiny particles, may be either sensitizing the lung area and/or esophagus and predisposing them to having those symptoms when they return home,” said Dr. Robertson, in an interview.
Particles in this size range may be able to bypass the protected areas of the nose and the lungs to reach the alveoli, where they could potentially interfere with the transfer of air between the lungs and the rest of the body, which could in turn lead to a variety of inflammatory conditions, according to Dr. Robertson.
She noted that particle exposure varies with a soldier’s wartime occupation, with higher exposures among mechanics and burn pit managers, for example. However, the highest levels of exposure do not predict later illness, which is a natural prompt for future research. “The second part of this whole pathophysiology is susceptibility. Is there something about those people that do get sick that makes them more susceptible than folks that don’t, even though they both have the same jobs?”
Dr. Pham and Dr. Robertson have no relevant financial disclosures.
, according to a new analysis of data from HCA Healthcare.
Not much work has been done on the overlap between the two conditions, both of which are believed to be driven by the action of both eosinophils and helper T cells, according to Linda Pham, DO, who presented the research at the annual meeting of the American College of Chest Physicians (CHEST).
“I have a colleague who is interested in GI and he’s really interested in EOE. We thought it would be nice to look at those populations of patients to see if there’s a correlation between them aside from just the atopic disease,” said Dr. Pham, who is an internal medicine resident at Riverside (Calif.) Community Hospital.
The findings underscore the need for assessing individual patient risk. “Having another concomitant disease like EoE, or maybe like atopic dermatitis, might cause you to have more severe [asthma] exacerbations causing you to go into the hospital more. I think if patients have more of these diseases, doctors can be more cognizant that they need to really be on top of treatment and make sure that [their patients] are aware of themselves so that if their symptoms exacerbate, they can go to the hospital and seek care,” said Dr. Pham.
The study was a retrospective analysis of 3,678,812 patients with asthma and 5,823 patients with both EoE and asthma. The data was drawn from 185 HCA hospitals, with records between 2016 and 2021.
The incidence of both asthma and asthma with EoE remained stable between 2016 and 2021. Dr. Pham pointed out that there are good methods to diagnose both conditions, which suggests that existing treatments are effective enough to be limiting the need for emergency treatment, according to Dr. Pham.
Among patients hospitalized with asthma alone, 72.55% were female, while 27.45% were male (P < .001). The numbers were much more evenly split among those with asthma and EoE, at 51.78% and 48.22%, respectively. The differing gender statistics aren’t easy to explain. “It’s not quite clear whether it’s because they just have more severe symptoms, or if it is other factors causing women to seek care more than their male counterparts. It could be personal biases, or it could be the asthma itself that is more severe in women,” said Dr. Pham.
When they broke down the analysis by sex, the researchers found that male EoE patients without asthma were a mean value of 5.517 years older than male EoE patients with asthma, and the mean difference was 5.480 years in female patients (P < .001 for both).
Although the direct cause of earlier hospitalization among patients with concomitant EoE and asthma is unclear, Dr. Pham speculated that the combination of atopic diseases may be leading to a stronger inflammatory response.
It remains to be seen if a similar relationship occurs with other atopic diseases, and future research could examine other factors. “I think it’d be good to look at not just age and gender, but BMI and occupation, things like that,” said Dr. Pham.
The study was of particular interest to Michelle Robertson, MD, who was in the audience. She is the director for clinical services at the Airborne Hazards and Burn Pits Center of Excellence at the New Jersey War-Related Illness and Injury Study Center. “We see a significant number of [veterans] who have been diagnosed with both asthma and eosinophilic esophagitis, and our thinking is that that is likely related to some of the military exposures: In particular, [what the] deployed veterans encountered in the Gulf War, [such as] the smoke from burn pits, sand and dust storms, and smoke from oil well fires. Our thinking is that the particulate matter, the PM 2.5, the very, very tiny particles, may be either sensitizing the lung area and/or esophagus and predisposing them to having those symptoms when they return home,” said Dr. Robertson, in an interview.
Particles in this size range may be able to bypass the protected areas of the nose and the lungs to reach the alveoli, where they could potentially interfere with the transfer of air between the lungs and the rest of the body, which could in turn lead to a variety of inflammatory conditions, according to Dr. Robertson.
She noted that particle exposure varies with a soldier’s wartime occupation, with higher exposures among mechanics and burn pit managers, for example. However, the highest levels of exposure do not predict later illness, which is a natural prompt for future research. “The second part of this whole pathophysiology is susceptibility. Is there something about those people that do get sick that makes them more susceptible than folks that don’t, even though they both have the same jobs?”
Dr. Pham and Dr. Robertson have no relevant financial disclosures.
FROM CHEST 2023
Treatment order evidence comes to light for premenopausal idiopathic osteoporosis: What to do after denosumab
VANCOUVER – With treatment with a bisphosphonate following sequential use of teriparatide (Forteo) and denosumab (Prolia) for premenopausal women with idiopathic osteoporosis, bone mineral density (BMD) was maintained over the first year following denosumab cessation, according to results from a small, nonrandomized extension of a phase 2 study.
Bisphosphonates are recommended for patients after they have completed a course of denosumab because cessation of the bone resorption blocker is known to increase bone turnover markers, decrease BMD, and raise the risk of vertebral fractures. Although there is evidence to support this treatment sequence for postmenopausal women, there was no evidence regarding premenopausal women with idiopathic osteoporosis, said Adi Cohen, MD, who presented the results of the study at the annual meeting of the American Society for Bone and Mineral Research.
In the extension study, neither length of treatment with denosumab nor transition to menopause affected BMD results. Weekly doses of alendronate (ALN) better suppressed C-terminal telopeptide (CTX) than did zoledronic acid (ZOL) and led to better maintenance of BMD than did a single dose of ZOL. The researchers suggested that single-dose ZOL may not prevent bone loss for an entire year.
It is too early to call the results practice changing, said Dr. Cohen, professor of medicine and endocrinology at Columbia University Irving Medical Center, New York, but she noted, “It’s important just to provide information about how sequences of osteoporosis medications might be used in a rare but certainly understudied group of premenopausal women with osteoporosis who need treatment, and these data hopefully will help make some treatment decisions.”
In the early 2000s, researchers initially believed that premenopausal women with low BMD had experienced some kind of temporary event and that they would likely improve on their own over time. “I think we now recognize that whatever it is that causes this is an ongoing issue and that this is a problem they’re going to have to deal with for the rest of their lives. This is something that they have to stay on top of,” said coauthor Elizabeth Shane, MD, who is a professor of medicine at CUIMC.
However, there are no practice guidelines for the management of osteoporosis in premenopausal women, according to Dr. Shane. She noted that there is controversy as to whether to treat women with low bone density who do not have a history of fractures. “I think that there’s pretty much agreement that anybody who has a lot of fractures has an early-onset form of osteoporosis. The controversy is what to do about the person who just has a low bone density and hasn’t yet fractured and what is the utility of trying to treat them at that point and perhaps prevent a fracture. I don’t think we have enough data to address that,” Dr. Shane said.
Still, the research has provided some clarity in her own practice. “I think if somebody would come to my office who had very low bone density, I would probably treat them. If they have fractures, I would definitely treat them. I think that our work has provided a framework for people to approach that,” she said.
The study was an extension of a sequential treatment approach that began with 2 years of teriparatide (20 mcg daily) followed by an extension study of 2–3 years of treatment with denosumab (60 mg every 6 months). Seven months after the last dose of denosumab, patients underwent 1 year of treatment with ALN (70 mg weekly; n = 18) or a single dose of ZOL (5 mg IV; n = 6), according to patient choice.
The original phase 2 study started with 41 women. At 24 months, teriparatide treatment led to BMD increases of 13% in the lumbar spine (LS), 5% in the total hip (TH), and 5% in the femoral neck (FN). There was a 2% decline in BMD in the forearm (distal radius [DR]). A group of 32 of the women participated in an extension study and took denosumab for 12 months. Of those patients, 29 continued to take it for another 12 months. At 12 months, BMD increased 5% in the LS, 3% in the TH, 3% in the FN, and 1% in the DR (P < .05 for all). At 24 months, BMD rose by 22%, 10%, and 10% at the first three of those locations. BMD in the DR remained stable, compared with the baseline after taking teriparatide.
The bisphosphonate phase of the extension study included 24 women (mean age, 43 years). The mean body mass index of the patients was 23.0 kg/m2. The patients had experienced a mean of 3.0 fractures in adulthood, and 38% of patients had a history of vertebral fracture.
Over 12 months of follow-up, the researchers found no statistically significant difference in BMD in the LS, TH, or FN, compared with bisphosphonate extension baseline. There was also no statistically significant change in serum CTX. There was evidence that, among patients with higher rates of bone turnover, there were higher rates of LS and FN bone loss during bisphosphonate treatment.
Among patients taking ZOL, at 12 months there was a statistically significant rise in CTX levels, but not among patients taking ALN. There were no new vertebral fractures among any participants during the bisphosphonate extension period.
The results represent critical data for an understudied population, according to Yumie Rhee, MD, PhD, who was comoderator of the session in which the study was presented. “They are showing that by using a bisphosphonate [patients] have this just slight decrease, but within error, so it’s maintaining the BMD, at least. I think it’s very important. It will be fascinating to see next year’s follow-up,” said Dr. Rhee, a professor of endocrinology at Yonsei University College of Medicine in Seoul, South Korea. “The problem with premenopausal osteoporosis is that we don’t have good evidence. Even though this study is very small, we’re just following that data, all of us.”
Comoderator Maria Zanchetta, MD, a professor of osteology at the Institute of Diagnostics and Metabolic Research, Universidad del Salvador, Buenos Aires, agreed. “We know what to do when we stop denosumab in postmenopausal women. We didn’t have any work about what to do when we stopped in premenopausal women. You can think that probably it’s going to be the same, but this is the first time you have the evidence that if you give bisphosphonate, you will maintain BMD.”
Limitations to the study include its small size and the lack of a placebo-treated control group. In addition, the bisphosphonate extension was not randomized.
The studies were funded by the U.S. Food and Drug Administration and Amgen. Dr. Cohen and Dr. Shane received research funding from Amgen. Dr. Rhee and Dr. Zanchetta have disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
VANCOUVER – With treatment with a bisphosphonate following sequential use of teriparatide (Forteo) and denosumab (Prolia) for premenopausal women with idiopathic osteoporosis, bone mineral density (BMD) was maintained over the first year following denosumab cessation, according to results from a small, nonrandomized extension of a phase 2 study.
Bisphosphonates are recommended for patients after they have completed a course of denosumab because cessation of the bone resorption blocker is known to increase bone turnover markers, decrease BMD, and raise the risk of vertebral fractures. Although there is evidence to support this treatment sequence for postmenopausal women, there was no evidence regarding premenopausal women with idiopathic osteoporosis, said Adi Cohen, MD, who presented the results of the study at the annual meeting of the American Society for Bone and Mineral Research.
In the extension study, neither length of treatment with denosumab nor transition to menopause affected BMD results. Weekly doses of alendronate (ALN) better suppressed C-terminal telopeptide (CTX) than did zoledronic acid (ZOL) and led to better maintenance of BMD than did a single dose of ZOL. The researchers suggested that single-dose ZOL may not prevent bone loss for an entire year.
It is too early to call the results practice changing, said Dr. Cohen, professor of medicine and endocrinology at Columbia University Irving Medical Center, New York, but she noted, “It’s important just to provide information about how sequences of osteoporosis medications might be used in a rare but certainly understudied group of premenopausal women with osteoporosis who need treatment, and these data hopefully will help make some treatment decisions.”
In the early 2000s, researchers initially believed that premenopausal women with low BMD had experienced some kind of temporary event and that they would likely improve on their own over time. “I think we now recognize that whatever it is that causes this is an ongoing issue and that this is a problem they’re going to have to deal with for the rest of their lives. This is something that they have to stay on top of,” said coauthor Elizabeth Shane, MD, who is a professor of medicine at CUIMC.
However, there are no practice guidelines for the management of osteoporosis in premenopausal women, according to Dr. Shane. She noted that there is controversy as to whether to treat women with low bone density who do not have a history of fractures. “I think that there’s pretty much agreement that anybody who has a lot of fractures has an early-onset form of osteoporosis. The controversy is what to do about the person who just has a low bone density and hasn’t yet fractured and what is the utility of trying to treat them at that point and perhaps prevent a fracture. I don’t think we have enough data to address that,” Dr. Shane said.
Still, the research has provided some clarity in her own practice. “I think if somebody would come to my office who had very low bone density, I would probably treat them. If they have fractures, I would definitely treat them. I think that our work has provided a framework for people to approach that,” she said.
The study was an extension of a sequential treatment approach that began with 2 years of teriparatide (20 mcg daily) followed by an extension study of 2–3 years of treatment with denosumab (60 mg every 6 months). Seven months after the last dose of denosumab, patients underwent 1 year of treatment with ALN (70 mg weekly; n = 18) or a single dose of ZOL (5 mg IV; n = 6), according to patient choice.
The original phase 2 study started with 41 women. At 24 months, teriparatide treatment led to BMD increases of 13% in the lumbar spine (LS), 5% in the total hip (TH), and 5% in the femoral neck (FN). There was a 2% decline in BMD in the forearm (distal radius [DR]). A group of 32 of the women participated in an extension study and took denosumab for 12 months. Of those patients, 29 continued to take it for another 12 months. At 12 months, BMD increased 5% in the LS, 3% in the TH, 3% in the FN, and 1% in the DR (P < .05 for all). At 24 months, BMD rose by 22%, 10%, and 10% at the first three of those locations. BMD in the DR remained stable, compared with the baseline after taking teriparatide.
The bisphosphonate phase of the extension study included 24 women (mean age, 43 years). The mean body mass index of the patients was 23.0 kg/m2. The patients had experienced a mean of 3.0 fractures in adulthood, and 38% of patients had a history of vertebral fracture.
Over 12 months of follow-up, the researchers found no statistically significant difference in BMD in the LS, TH, or FN, compared with bisphosphonate extension baseline. There was also no statistically significant change in serum CTX. There was evidence that, among patients with higher rates of bone turnover, there were higher rates of LS and FN bone loss during bisphosphonate treatment.
Among patients taking ZOL, at 12 months there was a statistically significant rise in CTX levels, but not among patients taking ALN. There were no new vertebral fractures among any participants during the bisphosphonate extension period.
The results represent critical data for an understudied population, according to Yumie Rhee, MD, PhD, who was comoderator of the session in which the study was presented. “They are showing that by using a bisphosphonate [patients] have this just slight decrease, but within error, so it’s maintaining the BMD, at least. I think it’s very important. It will be fascinating to see next year’s follow-up,” said Dr. Rhee, a professor of endocrinology at Yonsei University College of Medicine in Seoul, South Korea. “The problem with premenopausal osteoporosis is that we don’t have good evidence. Even though this study is very small, we’re just following that data, all of us.”
Comoderator Maria Zanchetta, MD, a professor of osteology at the Institute of Diagnostics and Metabolic Research, Universidad del Salvador, Buenos Aires, agreed. “We know what to do when we stop denosumab in postmenopausal women. We didn’t have any work about what to do when we stopped in premenopausal women. You can think that probably it’s going to be the same, but this is the first time you have the evidence that if you give bisphosphonate, you will maintain BMD.”
Limitations to the study include its small size and the lack of a placebo-treated control group. In addition, the bisphosphonate extension was not randomized.
The studies were funded by the U.S. Food and Drug Administration and Amgen. Dr. Cohen and Dr. Shane received research funding from Amgen. Dr. Rhee and Dr. Zanchetta have disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
VANCOUVER – With treatment with a bisphosphonate following sequential use of teriparatide (Forteo) and denosumab (Prolia) for premenopausal women with idiopathic osteoporosis, bone mineral density (BMD) was maintained over the first year following denosumab cessation, according to results from a small, nonrandomized extension of a phase 2 study.
Bisphosphonates are recommended for patients after they have completed a course of denosumab because cessation of the bone resorption blocker is known to increase bone turnover markers, decrease BMD, and raise the risk of vertebral fractures. Although there is evidence to support this treatment sequence for postmenopausal women, there was no evidence regarding premenopausal women with idiopathic osteoporosis, said Adi Cohen, MD, who presented the results of the study at the annual meeting of the American Society for Bone and Mineral Research.
In the extension study, neither length of treatment with denosumab nor transition to menopause affected BMD results. Weekly doses of alendronate (ALN) better suppressed C-terminal telopeptide (CTX) than did zoledronic acid (ZOL) and led to better maintenance of BMD than did a single dose of ZOL. The researchers suggested that single-dose ZOL may not prevent bone loss for an entire year.
It is too early to call the results practice changing, said Dr. Cohen, professor of medicine and endocrinology at Columbia University Irving Medical Center, New York, but she noted, “It’s important just to provide information about how sequences of osteoporosis medications might be used in a rare but certainly understudied group of premenopausal women with osteoporosis who need treatment, and these data hopefully will help make some treatment decisions.”
In the early 2000s, researchers initially believed that premenopausal women with low BMD had experienced some kind of temporary event and that they would likely improve on their own over time. “I think we now recognize that whatever it is that causes this is an ongoing issue and that this is a problem they’re going to have to deal with for the rest of their lives. This is something that they have to stay on top of,” said coauthor Elizabeth Shane, MD, who is a professor of medicine at CUIMC.
However, there are no practice guidelines for the management of osteoporosis in premenopausal women, according to Dr. Shane. She noted that there is controversy as to whether to treat women with low bone density who do not have a history of fractures. “I think that there’s pretty much agreement that anybody who has a lot of fractures has an early-onset form of osteoporosis. The controversy is what to do about the person who just has a low bone density and hasn’t yet fractured and what is the utility of trying to treat them at that point and perhaps prevent a fracture. I don’t think we have enough data to address that,” Dr. Shane said.
Still, the research has provided some clarity in her own practice. “I think if somebody would come to my office who had very low bone density, I would probably treat them. If they have fractures, I would definitely treat them. I think that our work has provided a framework for people to approach that,” she said.
The study was an extension of a sequential treatment approach that began with 2 years of teriparatide (20 mcg daily) followed by an extension study of 2–3 years of treatment with denosumab (60 mg every 6 months). Seven months after the last dose of denosumab, patients underwent 1 year of treatment with ALN (70 mg weekly; n = 18) or a single dose of ZOL (5 mg IV; n = 6), according to patient choice.
The original phase 2 study started with 41 women. At 24 months, teriparatide treatment led to BMD increases of 13% in the lumbar spine (LS), 5% in the total hip (TH), and 5% in the femoral neck (FN). There was a 2% decline in BMD in the forearm (distal radius [DR]). A group of 32 of the women participated in an extension study and took denosumab for 12 months. Of those patients, 29 continued to take it for another 12 months. At 12 months, BMD increased 5% in the LS, 3% in the TH, 3% in the FN, and 1% in the DR (P < .05 for all). At 24 months, BMD rose by 22%, 10%, and 10% at the first three of those locations. BMD in the DR remained stable, compared with the baseline after taking teriparatide.
The bisphosphonate phase of the extension study included 24 women (mean age, 43 years). The mean body mass index of the patients was 23.0 kg/m2. The patients had experienced a mean of 3.0 fractures in adulthood, and 38% of patients had a history of vertebral fracture.
Over 12 months of follow-up, the researchers found no statistically significant difference in BMD in the LS, TH, or FN, compared with bisphosphonate extension baseline. There was also no statistically significant change in serum CTX. There was evidence that, among patients with higher rates of bone turnover, there were higher rates of LS and FN bone loss during bisphosphonate treatment.
Among patients taking ZOL, at 12 months there was a statistically significant rise in CTX levels, but not among patients taking ALN. There were no new vertebral fractures among any participants during the bisphosphonate extension period.
The results represent critical data for an understudied population, according to Yumie Rhee, MD, PhD, who was comoderator of the session in which the study was presented. “They are showing that by using a bisphosphonate [patients] have this just slight decrease, but within error, so it’s maintaining the BMD, at least. I think it’s very important. It will be fascinating to see next year’s follow-up,” said Dr. Rhee, a professor of endocrinology at Yonsei University College of Medicine in Seoul, South Korea. “The problem with premenopausal osteoporosis is that we don’t have good evidence. Even though this study is very small, we’re just following that data, all of us.”
Comoderator Maria Zanchetta, MD, a professor of osteology at the Institute of Diagnostics and Metabolic Research, Universidad del Salvador, Buenos Aires, agreed. “We know what to do when we stop denosumab in postmenopausal women. We didn’t have any work about what to do when we stopped in premenopausal women. You can think that probably it’s going to be the same, but this is the first time you have the evidence that if you give bisphosphonate, you will maintain BMD.”
Limitations to the study include its small size and the lack of a placebo-treated control group. In addition, the bisphosphonate extension was not randomized.
The studies were funded by the U.S. Food and Drug Administration and Amgen. Dr. Cohen and Dr. Shane received research funding from Amgen. Dr. Rhee and Dr. Zanchetta have disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
AT ASBMR 2023
Higher fracture risk not seen with SGLT2 inhibitors
VANCOUVER – In patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors as an adjunct to metformin were not associated with an increase in fracture risk, according to a new real-world study.
There have been some reports of an increase in fracture risk associated with SGLT2 inhibitors, and it was observed in the phase 3 CANVAS trial of canagliflozin (Invokana), which led to a Food and Drug Administration warning of fracture risks associated with canagliflozin use. Some ensuing studies did not show an increased risk, but these studies were generally less than a year in duration and may have missed longer-term risk, according to Veerle van Hulten, MSc.
“Fracture risk is something that takes a long time to develop, so we wanted to have a longer follow-up. We looked into the CPRD [Clinical Practice Research Datalink], which is a beautiful database containing real-world data from primary care practices,” said Ms. van Hulten, a PhD student at Maastricht (the Netherlands) University, who presented the study at the annual meeting of the American Society for Bone and Mineral Research.
Ms. van Hulten and colleagues compared SGLT2 inhibitors with dipeptidyl peptidase–4 (DPP-4) inhibitors because the latter are used in similar populations and have been shown to have no effect on fracture risk.
“What we found is that SGLT2 inhibitors are not associated with an increased fracture risk. Even with a duration of use of over 811 days, we did not observe an increased hazard ratio for fractures when compared DPP-4 inhibitor users,” Ms. van Hulten said.
SGLT2 inhibitors reduce blood sugar by increasing elimination of sugar in the urine. They also increase phosphate, reduce calcium, and increase parathyroid hormone, which could in turn negatively affect bone turnover, according to Ms. van Hulten.
In the new study, conducted between January 2013 and June 2020, the researchers used propensity score matching to compare adult patients, including 13,807 who were prescribed SGLT2 inhibitors and 28,524 who were prescribed DPP-4 inhibitors for the first time. They matched patients based on demographics, comorbidities, comedication, and lifestyle factors.
There was no association between SGLT2 inhibitor use and overall fracture risk or major osteoporotic, hip, vertebral, humerus, radius, or ulna fractures. There was no difference in risk for any duration of use, even with the longest duration of use of 811 days (adjusted hazard ratio, 1.0). There were no differences among specific SGLT2 inhibitors, including canagliflozin (aHR, 1.12; 95% confidence interval, 0.73-1.72). Analyses by sex and age also revealed no statistically significant differences between the two drug classes.
During the Q&A session after the presentation, Sarah Berry, MD, MPH, an associate professor of medicine at Harvard Medical School and a clinical researcher at the Marcus Institute for Aging Research, both in Boston, noted the trend toward an increase in fracture risk in the first 90 days. “It looked like there was something going on in the first 90 days, and then after that the results were much closer to the null. I would put out maybe another potential mechanism whereby the SGLT2 inhibitors might cause fracture, and that’s falls. They cause polyuria, and any drug you give that causes women to rush to the bathroom may well cause fractures, particularly in the short term,” Dr. Berry said.
Ms. van Hulten agreed, and also brought up that the drugs can cause osmotic diuresis. That can lead to hypovolemia, the symptoms of which include weakness, fatigue, and dizziness. “And increased falls, of course, increases fracture risk. We do not expect anything to happen to bone metabolism in the first 90 days. I think we can agree that there would be more time needed to alter the bone enough to increase fracture risk, so we expect that this trend toward an increased risk might be attributable to that increased fall risk that might occur with SGLT2 inhibitor use,” she said.
It’s possible that such a mechanism explains increased fracture risk seen in some earlier short-term studies, she added.
Overall, Ms. van Hulten said that the results should provide some confidence in SGLT2 inhibitors, though more work needs to be done. “I think we provide reassurance that SGLT2 inhibitors are safe to use. However, we still only have a median follow-up of 1.6 years. It’s not as long as we maybe would like, but it’s the best we can do with the data available, since the SGLT2 inhibitors have only been used since 2013. So maybe it’s best to prescribe it and keep [fall risk] in mind and look into the effects later on again, but it seems to be safe to use.”
The study received funding from the Novo Nordisk Foundation. Ms. van Hulten and Dr. Berry reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
VANCOUVER – In patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors as an adjunct to metformin were not associated with an increase in fracture risk, according to a new real-world study.
There have been some reports of an increase in fracture risk associated with SGLT2 inhibitors, and it was observed in the phase 3 CANVAS trial of canagliflozin (Invokana), which led to a Food and Drug Administration warning of fracture risks associated with canagliflozin use. Some ensuing studies did not show an increased risk, but these studies were generally less than a year in duration and may have missed longer-term risk, according to Veerle van Hulten, MSc.
“Fracture risk is something that takes a long time to develop, so we wanted to have a longer follow-up. We looked into the CPRD [Clinical Practice Research Datalink], which is a beautiful database containing real-world data from primary care practices,” said Ms. van Hulten, a PhD student at Maastricht (the Netherlands) University, who presented the study at the annual meeting of the American Society for Bone and Mineral Research.
Ms. van Hulten and colleagues compared SGLT2 inhibitors with dipeptidyl peptidase–4 (DPP-4) inhibitors because the latter are used in similar populations and have been shown to have no effect on fracture risk.
“What we found is that SGLT2 inhibitors are not associated with an increased fracture risk. Even with a duration of use of over 811 days, we did not observe an increased hazard ratio for fractures when compared DPP-4 inhibitor users,” Ms. van Hulten said.
SGLT2 inhibitors reduce blood sugar by increasing elimination of sugar in the urine. They also increase phosphate, reduce calcium, and increase parathyroid hormone, which could in turn negatively affect bone turnover, according to Ms. van Hulten.
In the new study, conducted between January 2013 and June 2020, the researchers used propensity score matching to compare adult patients, including 13,807 who were prescribed SGLT2 inhibitors and 28,524 who were prescribed DPP-4 inhibitors for the first time. They matched patients based on demographics, comorbidities, comedication, and lifestyle factors.
There was no association between SGLT2 inhibitor use and overall fracture risk or major osteoporotic, hip, vertebral, humerus, radius, or ulna fractures. There was no difference in risk for any duration of use, even with the longest duration of use of 811 days (adjusted hazard ratio, 1.0). There were no differences among specific SGLT2 inhibitors, including canagliflozin (aHR, 1.12; 95% confidence interval, 0.73-1.72). Analyses by sex and age also revealed no statistically significant differences between the two drug classes.
During the Q&A session after the presentation, Sarah Berry, MD, MPH, an associate professor of medicine at Harvard Medical School and a clinical researcher at the Marcus Institute for Aging Research, both in Boston, noted the trend toward an increase in fracture risk in the first 90 days. “It looked like there was something going on in the first 90 days, and then after that the results were much closer to the null. I would put out maybe another potential mechanism whereby the SGLT2 inhibitors might cause fracture, and that’s falls. They cause polyuria, and any drug you give that causes women to rush to the bathroom may well cause fractures, particularly in the short term,” Dr. Berry said.
Ms. van Hulten agreed, and also brought up that the drugs can cause osmotic diuresis. That can lead to hypovolemia, the symptoms of which include weakness, fatigue, and dizziness. “And increased falls, of course, increases fracture risk. We do not expect anything to happen to bone metabolism in the first 90 days. I think we can agree that there would be more time needed to alter the bone enough to increase fracture risk, so we expect that this trend toward an increased risk might be attributable to that increased fall risk that might occur with SGLT2 inhibitor use,” she said.
It’s possible that such a mechanism explains increased fracture risk seen in some earlier short-term studies, she added.
Overall, Ms. van Hulten said that the results should provide some confidence in SGLT2 inhibitors, though more work needs to be done. “I think we provide reassurance that SGLT2 inhibitors are safe to use. However, we still only have a median follow-up of 1.6 years. It’s not as long as we maybe would like, but it’s the best we can do with the data available, since the SGLT2 inhibitors have only been used since 2013. So maybe it’s best to prescribe it and keep [fall risk] in mind and look into the effects later on again, but it seems to be safe to use.”
The study received funding from the Novo Nordisk Foundation. Ms. van Hulten and Dr. Berry reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
VANCOUVER – In patients with type 2 diabetes, sodium-glucose cotransporter 2 (SGLT2) inhibitors as an adjunct to metformin were not associated with an increase in fracture risk, according to a new real-world study.
There have been some reports of an increase in fracture risk associated with SGLT2 inhibitors, and it was observed in the phase 3 CANVAS trial of canagliflozin (Invokana), which led to a Food and Drug Administration warning of fracture risks associated with canagliflozin use. Some ensuing studies did not show an increased risk, but these studies were generally less than a year in duration and may have missed longer-term risk, according to Veerle van Hulten, MSc.
“Fracture risk is something that takes a long time to develop, so we wanted to have a longer follow-up. We looked into the CPRD [Clinical Practice Research Datalink], which is a beautiful database containing real-world data from primary care practices,” said Ms. van Hulten, a PhD student at Maastricht (the Netherlands) University, who presented the study at the annual meeting of the American Society for Bone and Mineral Research.
Ms. van Hulten and colleagues compared SGLT2 inhibitors with dipeptidyl peptidase–4 (DPP-4) inhibitors because the latter are used in similar populations and have been shown to have no effect on fracture risk.
“What we found is that SGLT2 inhibitors are not associated with an increased fracture risk. Even with a duration of use of over 811 days, we did not observe an increased hazard ratio for fractures when compared DPP-4 inhibitor users,” Ms. van Hulten said.
SGLT2 inhibitors reduce blood sugar by increasing elimination of sugar in the urine. They also increase phosphate, reduce calcium, and increase parathyroid hormone, which could in turn negatively affect bone turnover, according to Ms. van Hulten.
In the new study, conducted between January 2013 and June 2020, the researchers used propensity score matching to compare adult patients, including 13,807 who were prescribed SGLT2 inhibitors and 28,524 who were prescribed DPP-4 inhibitors for the first time. They matched patients based on demographics, comorbidities, comedication, and lifestyle factors.
There was no association between SGLT2 inhibitor use and overall fracture risk or major osteoporotic, hip, vertebral, humerus, radius, or ulna fractures. There was no difference in risk for any duration of use, even with the longest duration of use of 811 days (adjusted hazard ratio, 1.0). There were no differences among specific SGLT2 inhibitors, including canagliflozin (aHR, 1.12; 95% confidence interval, 0.73-1.72). Analyses by sex and age also revealed no statistically significant differences between the two drug classes.
During the Q&A session after the presentation, Sarah Berry, MD, MPH, an associate professor of medicine at Harvard Medical School and a clinical researcher at the Marcus Institute for Aging Research, both in Boston, noted the trend toward an increase in fracture risk in the first 90 days. “It looked like there was something going on in the first 90 days, and then after that the results were much closer to the null. I would put out maybe another potential mechanism whereby the SGLT2 inhibitors might cause fracture, and that’s falls. They cause polyuria, and any drug you give that causes women to rush to the bathroom may well cause fractures, particularly in the short term,” Dr. Berry said.
Ms. van Hulten agreed, and also brought up that the drugs can cause osmotic diuresis. That can lead to hypovolemia, the symptoms of which include weakness, fatigue, and dizziness. “And increased falls, of course, increases fracture risk. We do not expect anything to happen to bone metabolism in the first 90 days. I think we can agree that there would be more time needed to alter the bone enough to increase fracture risk, so we expect that this trend toward an increased risk might be attributable to that increased fall risk that might occur with SGLT2 inhibitor use,” she said.
It’s possible that such a mechanism explains increased fracture risk seen in some earlier short-term studies, she added.
Overall, Ms. van Hulten said that the results should provide some confidence in SGLT2 inhibitors, though more work needs to be done. “I think we provide reassurance that SGLT2 inhibitors are safe to use. However, we still only have a median follow-up of 1.6 years. It’s not as long as we maybe would like, but it’s the best we can do with the data available, since the SGLT2 inhibitors have only been used since 2013. So maybe it’s best to prescribe it and keep [fall risk] in mind and look into the effects later on again, but it seems to be safe to use.”
The study received funding from the Novo Nordisk Foundation. Ms. van Hulten and Dr. Berry reported no relevant financial relationships.
A version of this article appeared on Medscape.com.
AT ASBMR 2023
Fractures beget fractures at any age
VANCOUVER – The occurrence of a fracture predicts future fracture risk, but the increase in risk is the same no matter what the age of the patient, according to a new population-based study drawn from the Manitoba BMD Registry.
The work expands previous studies that focused mostly on fracture risk prediction after a first fracture among individuals aged 45-50 and older. Other limitations of prior studies include large age categories (such as “premenopausal”), reliance on self-reporting, and small sample sizes.
As a result, some guidelines recommend considering fracture history only for patients older than a certain age when assessing for future risk, such as with the Fracture Risk Assessment Tool (FRAX). The new study suggests a potential need to reconsider that stance.
“The [percentage] of increased risk from having had prevalent fractures in the past, no matter what your age, is about the same. I think that it’s really paradigm shifting because [when] most of us think [of] young people who fracture, we’re not thinking of osteoporosis or future fracture risk. We’re not saying, ‘Oh, I had a fracture when I was 25. When I’m 70, I should be thinking about osteoporosis.’ So, I think this study is quite eye-opening that way,” Carrie Ye, MD, who presented the study at the annual meeting of the American Society for Bone and Mineral Research, said in an interview.
Participants of younger age who are referred for dual-energy x-ray absorptiometry (DXA) likely represent a population at increased risk of osteoporosis, according to Dr. Ye. “Maybe they have Crohn’s disease or maybe they’re on a bunch of steroids, and so a clinician has flagged them,” said Dr. Ye, who is an assistant professor and rheumatologist at the University of Alberta, Edmonton.
The researchers limited the analysis to nontraumatic fractures, but session moderator Nicholas Harvey, MD, PhD, wondered if a similar finding would occur with traumatic fractures. In an interview, he noted that researchers led by William Leslie, MD, at the University of Manitoba, Winnipeg, found that prior traumatic fracture also predicted future low bone-mineral density (BMD) and osteoporotic fracture. “I think that would have been one interesting question,” said Dr. Harvey, director of the Medical Research Council Lifecourse Epidemiology Centre at the University of Southampton, England.
Dr. Ye’s study included 88,696 individuals who underwent a first DXA scan between 1996 and 2018, which researchers then linked to provincial administrative health data collected between 1979 and 2018. The mean age at first DXA was 64.6 years, and 90.3% were women. Their mean body mass index was 27.4 kg/m2. Current smokers made up 10.1% of the cohort, 5.5% had a history of prolonged glucocorticoid use, 3.1% had rheumatoid arthritis, and among 14.9% of patients, there was a secondary cause of osteoporosis. Over a median 25.1 years of observation prior to DXA, clinical fracture occurred in 23.8% of participants.
The mean age of the patients at the time of their first prior fracture was 57.7 years. Over a mean 9.0 years of follow-up, 14.6% of participants experienced a fracture of any kind, 14.0% had osteoporotic fractures, 10.6% had a major osteoporotic fracture (nonankle), and 3.5% had a hip fracture. Among persons aged 20-29 years to 80 years or older, the adjusted hazard ratios for future fractures were similar, ranging from 1.51 to 2.12 (P for trend = .120).
The results were similar when age groups were analyzed with regard to all fractures, osteoporotic fractures, major osteoporotic fractures, or hip fractures.
Going forward, Dr. Ye hopes to expand the research into childhood fractures. “They can break their bones pretty easily, especially as they’re going through growth spurts and things like that,” she said.
Asked what her advice to physicians would be, Dr. Ye responded: “Don’t ignore prior fractures, even if they occurred at an early age. I think if someone’s had a fracture, they bought themselves a fracture risk assessment, and that doesn’t mean necessarily a DXA scan. It means you go through their other risk factors: What medications are they on? Do they have a family history? Are they super low BMI? Look at other reasons why you should be worried about their bones, and if you should be worried about their bones, certainly [measure their] BMD and see what’s going on.”
Dr. Ye and Dr. Harvey have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VANCOUVER – The occurrence of a fracture predicts future fracture risk, but the increase in risk is the same no matter what the age of the patient, according to a new population-based study drawn from the Manitoba BMD Registry.
The work expands previous studies that focused mostly on fracture risk prediction after a first fracture among individuals aged 45-50 and older. Other limitations of prior studies include large age categories (such as “premenopausal”), reliance on self-reporting, and small sample sizes.
As a result, some guidelines recommend considering fracture history only for patients older than a certain age when assessing for future risk, such as with the Fracture Risk Assessment Tool (FRAX). The new study suggests a potential need to reconsider that stance.
“The [percentage] of increased risk from having had prevalent fractures in the past, no matter what your age, is about the same. I think that it’s really paradigm shifting because [when] most of us think [of] young people who fracture, we’re not thinking of osteoporosis or future fracture risk. We’re not saying, ‘Oh, I had a fracture when I was 25. When I’m 70, I should be thinking about osteoporosis.’ So, I think this study is quite eye-opening that way,” Carrie Ye, MD, who presented the study at the annual meeting of the American Society for Bone and Mineral Research, said in an interview.
Participants of younger age who are referred for dual-energy x-ray absorptiometry (DXA) likely represent a population at increased risk of osteoporosis, according to Dr. Ye. “Maybe they have Crohn’s disease or maybe they’re on a bunch of steroids, and so a clinician has flagged them,” said Dr. Ye, who is an assistant professor and rheumatologist at the University of Alberta, Edmonton.
The researchers limited the analysis to nontraumatic fractures, but session moderator Nicholas Harvey, MD, PhD, wondered if a similar finding would occur with traumatic fractures. In an interview, he noted that researchers led by William Leslie, MD, at the University of Manitoba, Winnipeg, found that prior traumatic fracture also predicted future low bone-mineral density (BMD) and osteoporotic fracture. “I think that would have been one interesting question,” said Dr. Harvey, director of the Medical Research Council Lifecourse Epidemiology Centre at the University of Southampton, England.
Dr. Ye’s study included 88,696 individuals who underwent a first DXA scan between 1996 and 2018, which researchers then linked to provincial administrative health data collected between 1979 and 2018. The mean age at first DXA was 64.6 years, and 90.3% were women. Their mean body mass index was 27.4 kg/m2. Current smokers made up 10.1% of the cohort, 5.5% had a history of prolonged glucocorticoid use, 3.1% had rheumatoid arthritis, and among 14.9% of patients, there was a secondary cause of osteoporosis. Over a median 25.1 years of observation prior to DXA, clinical fracture occurred in 23.8% of participants.
The mean age of the patients at the time of their first prior fracture was 57.7 years. Over a mean 9.0 years of follow-up, 14.6% of participants experienced a fracture of any kind, 14.0% had osteoporotic fractures, 10.6% had a major osteoporotic fracture (nonankle), and 3.5% had a hip fracture. Among persons aged 20-29 years to 80 years or older, the adjusted hazard ratios for future fractures were similar, ranging from 1.51 to 2.12 (P for trend = .120).
The results were similar when age groups were analyzed with regard to all fractures, osteoporotic fractures, major osteoporotic fractures, or hip fractures.
Going forward, Dr. Ye hopes to expand the research into childhood fractures. “They can break their bones pretty easily, especially as they’re going through growth spurts and things like that,” she said.
Asked what her advice to physicians would be, Dr. Ye responded: “Don’t ignore prior fractures, even if they occurred at an early age. I think if someone’s had a fracture, they bought themselves a fracture risk assessment, and that doesn’t mean necessarily a DXA scan. It means you go through their other risk factors: What medications are they on? Do they have a family history? Are they super low BMI? Look at other reasons why you should be worried about their bones, and if you should be worried about their bones, certainly [measure their] BMD and see what’s going on.”
Dr. Ye and Dr. Harvey have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VANCOUVER – The occurrence of a fracture predicts future fracture risk, but the increase in risk is the same no matter what the age of the patient, according to a new population-based study drawn from the Manitoba BMD Registry.
The work expands previous studies that focused mostly on fracture risk prediction after a first fracture among individuals aged 45-50 and older. Other limitations of prior studies include large age categories (such as “premenopausal”), reliance on self-reporting, and small sample sizes.
As a result, some guidelines recommend considering fracture history only for patients older than a certain age when assessing for future risk, such as with the Fracture Risk Assessment Tool (FRAX). The new study suggests a potential need to reconsider that stance.
“The [percentage] of increased risk from having had prevalent fractures in the past, no matter what your age, is about the same. I think that it’s really paradigm shifting because [when] most of us think [of] young people who fracture, we’re not thinking of osteoporosis or future fracture risk. We’re not saying, ‘Oh, I had a fracture when I was 25. When I’m 70, I should be thinking about osteoporosis.’ So, I think this study is quite eye-opening that way,” Carrie Ye, MD, who presented the study at the annual meeting of the American Society for Bone and Mineral Research, said in an interview.
Participants of younger age who are referred for dual-energy x-ray absorptiometry (DXA) likely represent a population at increased risk of osteoporosis, according to Dr. Ye. “Maybe they have Crohn’s disease or maybe they’re on a bunch of steroids, and so a clinician has flagged them,” said Dr. Ye, who is an assistant professor and rheumatologist at the University of Alberta, Edmonton.
The researchers limited the analysis to nontraumatic fractures, but session moderator Nicholas Harvey, MD, PhD, wondered if a similar finding would occur with traumatic fractures. In an interview, he noted that researchers led by William Leslie, MD, at the University of Manitoba, Winnipeg, found that prior traumatic fracture also predicted future low bone-mineral density (BMD) and osteoporotic fracture. “I think that would have been one interesting question,” said Dr. Harvey, director of the Medical Research Council Lifecourse Epidemiology Centre at the University of Southampton, England.
Dr. Ye’s study included 88,696 individuals who underwent a first DXA scan between 1996 and 2018, which researchers then linked to provincial administrative health data collected between 1979 and 2018. The mean age at first DXA was 64.6 years, and 90.3% were women. Their mean body mass index was 27.4 kg/m2. Current smokers made up 10.1% of the cohort, 5.5% had a history of prolonged glucocorticoid use, 3.1% had rheumatoid arthritis, and among 14.9% of patients, there was a secondary cause of osteoporosis. Over a median 25.1 years of observation prior to DXA, clinical fracture occurred in 23.8% of participants.
The mean age of the patients at the time of their first prior fracture was 57.7 years. Over a mean 9.0 years of follow-up, 14.6% of participants experienced a fracture of any kind, 14.0% had osteoporotic fractures, 10.6% had a major osteoporotic fracture (nonankle), and 3.5% had a hip fracture. Among persons aged 20-29 years to 80 years or older, the adjusted hazard ratios for future fractures were similar, ranging from 1.51 to 2.12 (P for trend = .120).
The results were similar when age groups were analyzed with regard to all fractures, osteoporotic fractures, major osteoporotic fractures, or hip fractures.
Going forward, Dr. Ye hopes to expand the research into childhood fractures. “They can break their bones pretty easily, especially as they’re going through growth spurts and things like that,” she said.
Asked what her advice to physicians would be, Dr. Ye responded: “Don’t ignore prior fractures, even if they occurred at an early age. I think if someone’s had a fracture, they bought themselves a fracture risk assessment, and that doesn’t mean necessarily a DXA scan. It means you go through their other risk factors: What medications are they on? Do they have a family history? Are they super low BMI? Look at other reasons why you should be worried about their bones, and if you should be worried about their bones, certainly [measure their] BMD and see what’s going on.”
Dr. Ye and Dr. Harvey have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ASBMR 2023
Greater fracture risk reduction seen with denosumab vs. zoledronic acid in postmenopausal women
VANCOUVER –
A previous head-to-head comparison showed that denosumab increased bone mineral density at key skeletal sites compared with zoledronic acid, but only a single, small observational study has examined fracture risk, and it found no difference.
The new study, presented at the annual meeting of the American Society for Bone and Mineral Research, used a relatively new method of real-world comparative effectiveness analysis called negative control outcome (NCO) to analyze Medicare fee-for-service data.
NCO analysis takes extra pains to remove bias through data that might be linked to potential confounders but could not reasonably be attributed to a drug. For example, people who have greater contact with the health care system may be more likely to get one drug or another. The researchers used the frequency of receiving a flu or pneumonia vaccine as a proxy for this. If the two comparison groups had a significant difference in a proxy, it suggested a hidden bias and forced the researchers to abandon those groupings. Another example used car accidents as a proxy for cognitive impairment.
“If you find meaningful differences between the two groups, and you can say there’s no way a bone drug could account for these differences, then we shouldn’t do this analysis because these groups just aren’t comparable. They probably differ by that confounding factor we couldn’t measure,” said Jeffrey Curtis, MD, who presented the study. He is a professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham.
The study strongly suggests superiority for denosumab. “There was a significant difference in multiple different groupings of fractures – beginning at year 2, extending to year 3 and even out to year 5 – that showed that there is a significant reduction in fracture risk if you get treated with denosumab [that was greater] than if you get treated with zoledronic acid,” Dr. Curtis said.
The researchers weighed 118 covariates and ultimately identified a population of 90,805 women taking denosumab and 37,328 taking zoledronic acid that was equally balanced in all patient characteristics. The mean age was about 75 years in the denosumab group and 74 in the zoledronic acid group.
The researchers found a 34% lower risk for hip fracture in the denosumab group by 5 years (relative risk, 0.66; 95% confidence interval, 0.43-0.90).
Similar patterns in fracture risk reduction were observed at 5 years for nonvertebral fracture (RR, 0.67; 95% CI, 0.52-0.82), nonhip nonvertebral fracture (RR, 0.69; 95% CI, 0.50-0.88), and major osteoporotic fracture (RR, 0.74; 95% CI, 0.59-0.89).
During the Q&A session after the talk, one audience member commented that the study was limited because the researchers only followed patients who received zoledronic acid for 60 days, which could have missed potential long-term benefits of the drug, especially since bisphosphonates have a lengthy skeletal retention time. Dr. Curtis acknowledged the point but said, “Usually, that’s not something we do, but these are different enough mechanisms of action that it may be warranted at least as a sensitivity analysis,” he said.
The study and its methodology were impressive, according to Yumie Rhee, MD, who comoderated the session where the study was presented. “I think they did a really good job by doing the negative control analysis. We’re not going to have a head-to-head clinical trial, so we don’t know the real fracture reduction differences [between denosumab and zoledronic acid]. [The NCO analysis] is more than the propensity matching score that we do usually,” said Dr. Rhee, who is a professor of endocrinology at Yonsei University College of Medicine in Seoul, South Korea.
In particular, the study showed a significantly greater reduction in hip fractures with denosumab. “Even in the RCTs, it was really hard to see the reduction in hip fracture, so I think this is showing much stronger data for denosumab. Especially in patients who have more [general fracture] risk and patients with higher hip fracture risk, I would go with denosumab,” Dr. Rhee said.
Her comoderator, Maria Zanchetta, MD, agreed. “It can have clinical implication, because we think denosumab is better than [zoledronic acid] for higher-risk patients, but we didn’t have the evidence. So at least we have a new [study] to look at, and I think it’s very important for our practice,” said Dr. Zanchetta, who is a professor of osteology at the Institute of Diagnostics and Metabolic Research, Universidad del Salvador, Buenos Aires.
The study was funded by Amgen, which markets denosumab. Dr. Curtis has consulted for Amgen. Dr. Rhee and Dr. Zanchetta report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VANCOUVER –
A previous head-to-head comparison showed that denosumab increased bone mineral density at key skeletal sites compared with zoledronic acid, but only a single, small observational study has examined fracture risk, and it found no difference.
The new study, presented at the annual meeting of the American Society for Bone and Mineral Research, used a relatively new method of real-world comparative effectiveness analysis called negative control outcome (NCO) to analyze Medicare fee-for-service data.
NCO analysis takes extra pains to remove bias through data that might be linked to potential confounders but could not reasonably be attributed to a drug. For example, people who have greater contact with the health care system may be more likely to get one drug or another. The researchers used the frequency of receiving a flu or pneumonia vaccine as a proxy for this. If the two comparison groups had a significant difference in a proxy, it suggested a hidden bias and forced the researchers to abandon those groupings. Another example used car accidents as a proxy for cognitive impairment.
“If you find meaningful differences between the two groups, and you can say there’s no way a bone drug could account for these differences, then we shouldn’t do this analysis because these groups just aren’t comparable. They probably differ by that confounding factor we couldn’t measure,” said Jeffrey Curtis, MD, who presented the study. He is a professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham.
The study strongly suggests superiority for denosumab. “There was a significant difference in multiple different groupings of fractures – beginning at year 2, extending to year 3 and even out to year 5 – that showed that there is a significant reduction in fracture risk if you get treated with denosumab [that was greater] than if you get treated with zoledronic acid,” Dr. Curtis said.
The researchers weighed 118 covariates and ultimately identified a population of 90,805 women taking denosumab and 37,328 taking zoledronic acid that was equally balanced in all patient characteristics. The mean age was about 75 years in the denosumab group and 74 in the zoledronic acid group.
The researchers found a 34% lower risk for hip fracture in the denosumab group by 5 years (relative risk, 0.66; 95% confidence interval, 0.43-0.90).
Similar patterns in fracture risk reduction were observed at 5 years for nonvertebral fracture (RR, 0.67; 95% CI, 0.52-0.82), nonhip nonvertebral fracture (RR, 0.69; 95% CI, 0.50-0.88), and major osteoporotic fracture (RR, 0.74; 95% CI, 0.59-0.89).
During the Q&A session after the talk, one audience member commented that the study was limited because the researchers only followed patients who received zoledronic acid for 60 days, which could have missed potential long-term benefits of the drug, especially since bisphosphonates have a lengthy skeletal retention time. Dr. Curtis acknowledged the point but said, “Usually, that’s not something we do, but these are different enough mechanisms of action that it may be warranted at least as a sensitivity analysis,” he said.
The study and its methodology were impressive, according to Yumie Rhee, MD, who comoderated the session where the study was presented. “I think they did a really good job by doing the negative control analysis. We’re not going to have a head-to-head clinical trial, so we don’t know the real fracture reduction differences [between denosumab and zoledronic acid]. [The NCO analysis] is more than the propensity matching score that we do usually,” said Dr. Rhee, who is a professor of endocrinology at Yonsei University College of Medicine in Seoul, South Korea.
In particular, the study showed a significantly greater reduction in hip fractures with denosumab. “Even in the RCTs, it was really hard to see the reduction in hip fracture, so I think this is showing much stronger data for denosumab. Especially in patients who have more [general fracture] risk and patients with higher hip fracture risk, I would go with denosumab,” Dr. Rhee said.
Her comoderator, Maria Zanchetta, MD, agreed. “It can have clinical implication, because we think denosumab is better than [zoledronic acid] for higher-risk patients, but we didn’t have the evidence. So at least we have a new [study] to look at, and I think it’s very important for our practice,” said Dr. Zanchetta, who is a professor of osteology at the Institute of Diagnostics and Metabolic Research, Universidad del Salvador, Buenos Aires.
The study was funded by Amgen, which markets denosumab. Dr. Curtis has consulted for Amgen. Dr. Rhee and Dr. Zanchetta report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
VANCOUVER –
A previous head-to-head comparison showed that denosumab increased bone mineral density at key skeletal sites compared with zoledronic acid, but only a single, small observational study has examined fracture risk, and it found no difference.
The new study, presented at the annual meeting of the American Society for Bone and Mineral Research, used a relatively new method of real-world comparative effectiveness analysis called negative control outcome (NCO) to analyze Medicare fee-for-service data.
NCO analysis takes extra pains to remove bias through data that might be linked to potential confounders but could not reasonably be attributed to a drug. For example, people who have greater contact with the health care system may be more likely to get one drug or another. The researchers used the frequency of receiving a flu or pneumonia vaccine as a proxy for this. If the two comparison groups had a significant difference in a proxy, it suggested a hidden bias and forced the researchers to abandon those groupings. Another example used car accidents as a proxy for cognitive impairment.
“If you find meaningful differences between the two groups, and you can say there’s no way a bone drug could account for these differences, then we shouldn’t do this analysis because these groups just aren’t comparable. They probably differ by that confounding factor we couldn’t measure,” said Jeffrey Curtis, MD, who presented the study. He is a professor of medicine in the division of clinical immunology and rheumatology at the University of Alabama at Birmingham.
The study strongly suggests superiority for denosumab. “There was a significant difference in multiple different groupings of fractures – beginning at year 2, extending to year 3 and even out to year 5 – that showed that there is a significant reduction in fracture risk if you get treated with denosumab [that was greater] than if you get treated with zoledronic acid,” Dr. Curtis said.
The researchers weighed 118 covariates and ultimately identified a population of 90,805 women taking denosumab and 37,328 taking zoledronic acid that was equally balanced in all patient characteristics. The mean age was about 75 years in the denosumab group and 74 in the zoledronic acid group.
The researchers found a 34% lower risk for hip fracture in the denosumab group by 5 years (relative risk, 0.66; 95% confidence interval, 0.43-0.90).
Similar patterns in fracture risk reduction were observed at 5 years for nonvertebral fracture (RR, 0.67; 95% CI, 0.52-0.82), nonhip nonvertebral fracture (RR, 0.69; 95% CI, 0.50-0.88), and major osteoporotic fracture (RR, 0.74; 95% CI, 0.59-0.89).
During the Q&A session after the talk, one audience member commented that the study was limited because the researchers only followed patients who received zoledronic acid for 60 days, which could have missed potential long-term benefits of the drug, especially since bisphosphonates have a lengthy skeletal retention time. Dr. Curtis acknowledged the point but said, “Usually, that’s not something we do, but these are different enough mechanisms of action that it may be warranted at least as a sensitivity analysis,” he said.
The study and its methodology were impressive, according to Yumie Rhee, MD, who comoderated the session where the study was presented. “I think they did a really good job by doing the negative control analysis. We’re not going to have a head-to-head clinical trial, so we don’t know the real fracture reduction differences [between denosumab and zoledronic acid]. [The NCO analysis] is more than the propensity matching score that we do usually,” said Dr. Rhee, who is a professor of endocrinology at Yonsei University College of Medicine in Seoul, South Korea.
In particular, the study showed a significantly greater reduction in hip fractures with denosumab. “Even in the RCTs, it was really hard to see the reduction in hip fracture, so I think this is showing much stronger data for denosumab. Especially in patients who have more [general fracture] risk and patients with higher hip fracture risk, I would go with denosumab,” Dr. Rhee said.
Her comoderator, Maria Zanchetta, MD, agreed. “It can have clinical implication, because we think denosumab is better than [zoledronic acid] for higher-risk patients, but we didn’t have the evidence. So at least we have a new [study] to look at, and I think it’s very important for our practice,” said Dr. Zanchetta, who is a professor of osteology at the Institute of Diagnostics and Metabolic Research, Universidad del Salvador, Buenos Aires.
The study was funded by Amgen, which markets denosumab. Dr. Curtis has consulted for Amgen. Dr. Rhee and Dr. Zanchetta report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ASBMR 2023