User login
Dapagliflozin meets primary endpoint in the DAPA-HF trial
The SGLT2 inhibitor dapagliflozin (Farxiga) successfully met the primary endpoint of the phase 3 DAPA-HF trial in patients with heart failure, according to a press release from AstraZeneca.
DAPA-HF is an international, multicenter, parallel group, randomized, double-blind trial in patients with heart failure and reduced ejection fraction with or without type 2 diabetes. Patients in the study received either 10 mg dapagliflozin or placebo, and the primary outcome was time to a worsening heart failure event or to cardiovascular death. Patients who received dapagliflozin had a statistically significant reduction in incidence of cardiovascular death and an increase in time to a heart failure event.
The adverse events reported for dapagliflozin in DAPA-HF matched the established safety profile for the drug, AstraZeneca noted in the press release.
“The benefits of dapagliflozin in DAPA-HF are very impressive, with a substantial reduction in the primary composite outcome of cardiovascular death or hospital admission. We hope these exciting new findings will ultimately help reduce the terrible burden of disease caused by heart failure and help improve outcomes for our patients,” said John McMurray, MD, of the Institute of Cardiovascular and Medical Sciences at the University of Glasgow.
Another dapagliflozin trial, called DELIVER, is focused on 4,700 patients with heart failure with preserved ejection fraction randomized to dapagliflozin (Farxiga) or placebo. That is due to be completed next year.
The full results from DAPA-HF will be presented at a later date.
The SGLT2 inhibitor dapagliflozin (Farxiga) successfully met the primary endpoint of the phase 3 DAPA-HF trial in patients with heart failure, according to a press release from AstraZeneca.
DAPA-HF is an international, multicenter, parallel group, randomized, double-blind trial in patients with heart failure and reduced ejection fraction with or without type 2 diabetes. Patients in the study received either 10 mg dapagliflozin or placebo, and the primary outcome was time to a worsening heart failure event or to cardiovascular death. Patients who received dapagliflozin had a statistically significant reduction in incidence of cardiovascular death and an increase in time to a heart failure event.
The adverse events reported for dapagliflozin in DAPA-HF matched the established safety profile for the drug, AstraZeneca noted in the press release.
“The benefits of dapagliflozin in DAPA-HF are very impressive, with a substantial reduction in the primary composite outcome of cardiovascular death or hospital admission. We hope these exciting new findings will ultimately help reduce the terrible burden of disease caused by heart failure and help improve outcomes for our patients,” said John McMurray, MD, of the Institute of Cardiovascular and Medical Sciences at the University of Glasgow.
Another dapagliflozin trial, called DELIVER, is focused on 4,700 patients with heart failure with preserved ejection fraction randomized to dapagliflozin (Farxiga) or placebo. That is due to be completed next year.
The full results from DAPA-HF will be presented at a later date.
The SGLT2 inhibitor dapagliflozin (Farxiga) successfully met the primary endpoint of the phase 3 DAPA-HF trial in patients with heart failure, according to a press release from AstraZeneca.
DAPA-HF is an international, multicenter, parallel group, randomized, double-blind trial in patients with heart failure and reduced ejection fraction with or without type 2 diabetes. Patients in the study received either 10 mg dapagliflozin or placebo, and the primary outcome was time to a worsening heart failure event or to cardiovascular death. Patients who received dapagliflozin had a statistically significant reduction in incidence of cardiovascular death and an increase in time to a heart failure event.
The adverse events reported for dapagliflozin in DAPA-HF matched the established safety profile for the drug, AstraZeneca noted in the press release.
“The benefits of dapagliflozin in DAPA-HF are very impressive, with a substantial reduction in the primary composite outcome of cardiovascular death or hospital admission. We hope these exciting new findings will ultimately help reduce the terrible burden of disease caused by heart failure and help improve outcomes for our patients,” said John McMurray, MD, of the Institute of Cardiovascular and Medical Sciences at the University of Glasgow.
Another dapagliflozin trial, called DELIVER, is focused on 4,700 patients with heart failure with preserved ejection fraction randomized to dapagliflozin (Farxiga) or placebo. That is due to be completed next year.
The full results from DAPA-HF will be presented at a later date.
New biomarker model outmatches conventional risk factors for predicting mortality
A new model using 14 biomarkers may be more accurate at predicting longer-term mortality than a model comprising conventional risk factors, based on the largest metabolomics study to date.
The prognostic model was more accurate at predicting 5- and 10-year mortality across all ages, reported Joris Deelen, PhD, of Leiden (the Netherlands) University Medical Center and colleagues.
“These results suggest that metabolic biomarker profiling could potentially be used to guide patient care, if further validated in relevant clinical settings,” the investigators wrote in Nature Communications.
“There is no consensus on the ultimate set of predictors of longer-term [5-10 years] mortality risk, since the predictive power of the currently used risk factors is limited, especially at higher ages,” the investigators wrote. “However, it is especially this age group and follow-up time window for which a robust tool would aid clinicians in assessing whether treatment is still sensible.”
The current study was a survival meta-analysis of 44,168 individuals from 12 cohorts aged between 18 and 109 years at baseline. First, the investigators looked for associations between 226 metabolic biomarkers and all-cause mortality in the 5,512 people who died during follow-up. This revealed associations between mortality and 136 biomarkers, which increased to 159 biomarkers after adjusting for recently reported all-cause mortality associations with albumin, very low-density lipoprotein (VLDL) particle size, citrate, and glycoprotein acetyls. Because of strong correlations between many of the biomarkers evaluated, the investigators pared the field down to 63 biomarkers, then used a forward-backward procedure to ultimately identify 14 biomarkers independently associated with mortality. Of the four recently described biomarkers, citrate was excluded from the final model because of its minimal contribution to mortality estimates.
The 14 biomarkers were total lipids in chylomicrons and extremely large VLDL cholesterol, total lipids in small HDL cholesterol, mean diameter for VLDL cholesterol particles, ratio of polyunsaturated fatty acids to total fatty acids, glucose, lactate, histidine, isoleucine, leucine, valine, phenylalanine, acetoacetate, albumin, and glycoprotein acetyls.
“The 14 identified biomarkers are involved in various processes, such as lipoprotein and fatty acid metabolism, glycolysis, fluid balance, and inflammation. Although the majority of these biomarkers have been associated with mortality before, this is the first study that shows their independent effect when combined into one model,” the researchers wrote.
Implementation of the new biomarker model led to a score that typically ranged from –2 to 3. A 1-point increase was associated with a 173% increased risk of death (hazard ratio, 2.73; P less than 1 x 10–132). Analysis of cause-specific mortality revealed that most biomarkers were predictive of multiple causes of death. Some biomarkers were more focused; glucose, for example, was more predictive of cardiovascular-related death than of death because of cancer or nonlocalized infections. Compared with a model incorporating conventional risk factors, the biomarker model more accurately predicted 5- and 10-year mortality, with respective C-statistics of 0.837 versus 0.772 and 0.830 versus 0.790. This superiority was even more pronounced when only individuals aged older than 60 years were included.
The study was funded by Biobanking and BioMolecular resources Research Initiative–Netherlands. The investigators reported additional relationships with Nightingale Health, Novo Nordisk, and Bayer.
SOURCE: Deelen J et al. Nature Comm. 2019 Aug 20. doi: 10.1038/s41467-019-11311-9.
A new model using 14 biomarkers may be more accurate at predicting longer-term mortality than a model comprising conventional risk factors, based on the largest metabolomics study to date.
The prognostic model was more accurate at predicting 5- and 10-year mortality across all ages, reported Joris Deelen, PhD, of Leiden (the Netherlands) University Medical Center and colleagues.
“These results suggest that metabolic biomarker profiling could potentially be used to guide patient care, if further validated in relevant clinical settings,” the investigators wrote in Nature Communications.
“There is no consensus on the ultimate set of predictors of longer-term [5-10 years] mortality risk, since the predictive power of the currently used risk factors is limited, especially at higher ages,” the investigators wrote. “However, it is especially this age group and follow-up time window for which a robust tool would aid clinicians in assessing whether treatment is still sensible.”
The current study was a survival meta-analysis of 44,168 individuals from 12 cohorts aged between 18 and 109 years at baseline. First, the investigators looked for associations between 226 metabolic biomarkers and all-cause mortality in the 5,512 people who died during follow-up. This revealed associations between mortality and 136 biomarkers, which increased to 159 biomarkers after adjusting for recently reported all-cause mortality associations with albumin, very low-density lipoprotein (VLDL) particle size, citrate, and glycoprotein acetyls. Because of strong correlations between many of the biomarkers evaluated, the investigators pared the field down to 63 biomarkers, then used a forward-backward procedure to ultimately identify 14 biomarkers independently associated with mortality. Of the four recently described biomarkers, citrate was excluded from the final model because of its minimal contribution to mortality estimates.
The 14 biomarkers were total lipids in chylomicrons and extremely large VLDL cholesterol, total lipids in small HDL cholesterol, mean diameter for VLDL cholesterol particles, ratio of polyunsaturated fatty acids to total fatty acids, glucose, lactate, histidine, isoleucine, leucine, valine, phenylalanine, acetoacetate, albumin, and glycoprotein acetyls.
“The 14 identified biomarkers are involved in various processes, such as lipoprotein and fatty acid metabolism, glycolysis, fluid balance, and inflammation. Although the majority of these biomarkers have been associated with mortality before, this is the first study that shows their independent effect when combined into one model,” the researchers wrote.
Implementation of the new biomarker model led to a score that typically ranged from –2 to 3. A 1-point increase was associated with a 173% increased risk of death (hazard ratio, 2.73; P less than 1 x 10–132). Analysis of cause-specific mortality revealed that most biomarkers were predictive of multiple causes of death. Some biomarkers were more focused; glucose, for example, was more predictive of cardiovascular-related death than of death because of cancer or nonlocalized infections. Compared with a model incorporating conventional risk factors, the biomarker model more accurately predicted 5- and 10-year mortality, with respective C-statistics of 0.837 versus 0.772 and 0.830 versus 0.790. This superiority was even more pronounced when only individuals aged older than 60 years were included.
The study was funded by Biobanking and BioMolecular resources Research Initiative–Netherlands. The investigators reported additional relationships with Nightingale Health, Novo Nordisk, and Bayer.
SOURCE: Deelen J et al. Nature Comm. 2019 Aug 20. doi: 10.1038/s41467-019-11311-9.
A new model using 14 biomarkers may be more accurate at predicting longer-term mortality than a model comprising conventional risk factors, based on the largest metabolomics study to date.
The prognostic model was more accurate at predicting 5- and 10-year mortality across all ages, reported Joris Deelen, PhD, of Leiden (the Netherlands) University Medical Center and colleagues.
“These results suggest that metabolic biomarker profiling could potentially be used to guide patient care, if further validated in relevant clinical settings,” the investigators wrote in Nature Communications.
“There is no consensus on the ultimate set of predictors of longer-term [5-10 years] mortality risk, since the predictive power of the currently used risk factors is limited, especially at higher ages,” the investigators wrote. “However, it is especially this age group and follow-up time window for which a robust tool would aid clinicians in assessing whether treatment is still sensible.”
The current study was a survival meta-analysis of 44,168 individuals from 12 cohorts aged between 18 and 109 years at baseline. First, the investigators looked for associations between 226 metabolic biomarkers and all-cause mortality in the 5,512 people who died during follow-up. This revealed associations between mortality and 136 biomarkers, which increased to 159 biomarkers after adjusting for recently reported all-cause mortality associations with albumin, very low-density lipoprotein (VLDL) particle size, citrate, and glycoprotein acetyls. Because of strong correlations between many of the biomarkers evaluated, the investigators pared the field down to 63 biomarkers, then used a forward-backward procedure to ultimately identify 14 biomarkers independently associated with mortality. Of the four recently described biomarkers, citrate was excluded from the final model because of its minimal contribution to mortality estimates.
The 14 biomarkers were total lipids in chylomicrons and extremely large VLDL cholesterol, total lipids in small HDL cholesterol, mean diameter for VLDL cholesterol particles, ratio of polyunsaturated fatty acids to total fatty acids, glucose, lactate, histidine, isoleucine, leucine, valine, phenylalanine, acetoacetate, albumin, and glycoprotein acetyls.
“The 14 identified biomarkers are involved in various processes, such as lipoprotein and fatty acid metabolism, glycolysis, fluid balance, and inflammation. Although the majority of these biomarkers have been associated with mortality before, this is the first study that shows their independent effect when combined into one model,” the researchers wrote.
Implementation of the new biomarker model led to a score that typically ranged from –2 to 3. A 1-point increase was associated with a 173% increased risk of death (hazard ratio, 2.73; P less than 1 x 10–132). Analysis of cause-specific mortality revealed that most biomarkers were predictive of multiple causes of death. Some biomarkers were more focused; glucose, for example, was more predictive of cardiovascular-related death than of death because of cancer or nonlocalized infections. Compared with a model incorporating conventional risk factors, the biomarker model more accurately predicted 5- and 10-year mortality, with respective C-statistics of 0.837 versus 0.772 and 0.830 versus 0.790. This superiority was even more pronounced when only individuals aged older than 60 years were included.
The study was funded by Biobanking and BioMolecular resources Research Initiative–Netherlands. The investigators reported additional relationships with Nightingale Health, Novo Nordisk, and Bayer.
SOURCE: Deelen J et al. Nature Comm. 2019 Aug 20. doi: 10.1038/s41467-019-11311-9.
FROM NATURE COMMUNICATIONS
Key clinical point: A new model using 14 biomarkers may be more accurate at predicting 5- and 10-year mortality than a model comprising conventional risk factors.
Major finding: The biomarker model better predicted 5-year mortality than the conventional model (C-statistic, 0.837 vs. 0.772).
Study details: A retrospective metabolomics study involving 44,168 individuals.
Disclosures: The study was funded by Biobanking and BioMolecular Resources Research Initiative–Netherlands. The investigators reported additional relationships with Nightingale Health, Novo Nordisk, and Bayer.
Source: Deelen J et al. Nature Comm. 2019 Aug 20. doi: 10.1038/s41467-019-11311-9.
Self-reported falls can predict osteoporotic fracture risk
A single, simple question about a patient’s experience of falls in the previous year can help predict their risk of fractures, a study suggests.
In Osteoporosis International, researchers reported the outcomes of a cohort study using Manitoba clinical registry data from 24,943 men and women aged 40 years and older within the province who had undergone a fracture-probability assessment, and had data on self-reported falls for the previous year and fracture outcomes.
William D. Leslie, MD, of the University of Manitoba in Winnipeg, and coauthors wrote that a frequent criticism of the FRAX fracture risk assessment tool was the fact that it didn’t include falls or fall risk in predicting fractures.
“Recent evidence derived from carefully conducted research cohort studies in men found that falls increase fracture risk independent of FRAX probability,” they wrote. “However, data are inconsistent with a paucity of evidence demonstrating usefulness of self-reported fall data as collected in routine clinical practice.”
0.8% experienced a hip fracture, and 4.9% experienced any incident fracture.
The analysis showed an increased risk of fracture with the increasing number of self-reported falls experienced in the previous year. The risk of major osteoporotic fracture was 49% higher among individuals who reported one fall, 74% in those who reported two falls and 2.6-fold higher for those who reported three or more falls in the previous year, compared with those who did not report any falls.
A similar pattern was seen for any incident fracture and hip fracture, with a 3.4-fold higher risk of hip fracture seen in those who reported three or more falls. The study also showed an increase in mortality risk with increasing number of falls.
“We documented that a simple question regarding self-reported falls in the previous year could be easily collected during routine clinical practice and that this information was strongly predictive of short-term fracture risk independent of multiple clinical risk factors including fracture probability using the FRAX tool with BMD [bone mineral density],” the authors wrote.
The analysis did not find an interaction with age or sex and the number of falls.
John A. Kanis, MD, reported grants from Amgen, Lily, and Radius Health. Three other coauthors reported nothing to declare for the context of this article, but reported research grants, speaking honoraria, consultancies from a variety of pharmaceutical companies and organizations. The remaining five coauthors declared no conflicts of interest.
SOURCE: Leslie WD et al. Osteoporos Int. 2019 Aug. 2. doi: 10.1007/s00198-019-05106-3.
Fragility fractures remain a major contributor to morbidity and even mortality of aging populations. Concerted efforts of clinicians, epidemiologists, and researchers have yielded an assortment of diagnostic strategies and prognostic algorithms in efforts to identify individuals at fracture risk. A variety of demographic (age, sex), biological (family history, specific disorders and medications), anatomical (bone mineral density, body mass index), and behavioral (smoking, alcohol consumption) parameters are recognized as predictors of fracture risk, and often are incorporated in predictive algorithms for fracture predisposition. FRAX (Fracture Risk Assessment) is a widely used screening tool that is valid in offering fracture risk quantification across populations (Arch Osteoporos. 2016 Dec;11[1]:25; World Health Organization Assessment of Osteoporosis at the Primary Health Care Level).
Aging and accompanying neurocognitive deterioration, visual impairment, as well as iatrogenic factors are recognized to contribute to predisposition to falls in aging populations. A propensity for falls has long been regarded as a fracture risk (Curr Osteoporos Rep. 2008;6[4]:149-54). However, the evidence to support this logical assumption has been mixed with resulting exclusion of tendency to fall from commonly utilized fracture risk predictive models and tools. A predisposition to and frequency of falls is considered neither a risk modulator nor a mediator in the commonly utilized FRAX-based fracture risk assessments, and it is believed that fracture probability may be underestimated by FRAX in those predisposed to frequent falls (J Clin Densitom. 2011 Jul-Sep;14[3]:194–204).
The landscape of fracture risk assessment and quantification in the aforementioned backdrop has been refreshingly enhanced by a recent contribution by Leslie et al. wherein the authors provide real-life evidence relating self-reported falls to fracture risk. In a robust population sample nearing 25,000 women, increasing number of falls within the past year was associated with an increasing fracture risk, and this relationship persisted after adjusting for covariates that are recognized to predispose to fragility fractures, including age, body mass index, and bone mineral density. Women’s health providers are encouraged to familiarize themselves with the work of Leslie et al.; the authors’ message, that fall history be incorporated into risk quantification measures, is striking in its simplicity and profound in its preventative potential given that fall risk in and of itself may be mitigated in many through targeted interventions.
Lubna Pal, MBBS, MS, is professor and fellowship director of the division of reproductive endocrinology & infertility at Yale University, New Haven, Conn. She also is the director of the Yale reproductive endocrinology & infertility menopause program. She said she had no relevant financial disclosures. Email her at [email protected].
Fragility fractures remain a major contributor to morbidity and even mortality of aging populations. Concerted efforts of clinicians, epidemiologists, and researchers have yielded an assortment of diagnostic strategies and prognostic algorithms in efforts to identify individuals at fracture risk. A variety of demographic (age, sex), biological (family history, specific disorders and medications), anatomical (bone mineral density, body mass index), and behavioral (smoking, alcohol consumption) parameters are recognized as predictors of fracture risk, and often are incorporated in predictive algorithms for fracture predisposition. FRAX (Fracture Risk Assessment) is a widely used screening tool that is valid in offering fracture risk quantification across populations (Arch Osteoporos. 2016 Dec;11[1]:25; World Health Organization Assessment of Osteoporosis at the Primary Health Care Level).
Aging and accompanying neurocognitive deterioration, visual impairment, as well as iatrogenic factors are recognized to contribute to predisposition to falls in aging populations. A propensity for falls has long been regarded as a fracture risk (Curr Osteoporos Rep. 2008;6[4]:149-54). However, the evidence to support this logical assumption has been mixed with resulting exclusion of tendency to fall from commonly utilized fracture risk predictive models and tools. A predisposition to and frequency of falls is considered neither a risk modulator nor a mediator in the commonly utilized FRAX-based fracture risk assessments, and it is believed that fracture probability may be underestimated by FRAX in those predisposed to frequent falls (J Clin Densitom. 2011 Jul-Sep;14[3]:194–204).
The landscape of fracture risk assessment and quantification in the aforementioned backdrop has been refreshingly enhanced by a recent contribution by Leslie et al. wherein the authors provide real-life evidence relating self-reported falls to fracture risk. In a robust population sample nearing 25,000 women, increasing number of falls within the past year was associated with an increasing fracture risk, and this relationship persisted after adjusting for covariates that are recognized to predispose to fragility fractures, including age, body mass index, and bone mineral density. Women’s health providers are encouraged to familiarize themselves with the work of Leslie et al.; the authors’ message, that fall history be incorporated into risk quantification measures, is striking in its simplicity and profound in its preventative potential given that fall risk in and of itself may be mitigated in many through targeted interventions.
Lubna Pal, MBBS, MS, is professor and fellowship director of the division of reproductive endocrinology & infertility at Yale University, New Haven, Conn. She also is the director of the Yale reproductive endocrinology & infertility menopause program. She said she had no relevant financial disclosures. Email her at [email protected].
Fragility fractures remain a major contributor to morbidity and even mortality of aging populations. Concerted efforts of clinicians, epidemiologists, and researchers have yielded an assortment of diagnostic strategies and prognostic algorithms in efforts to identify individuals at fracture risk. A variety of demographic (age, sex), biological (family history, specific disorders and medications), anatomical (bone mineral density, body mass index), and behavioral (smoking, alcohol consumption) parameters are recognized as predictors of fracture risk, and often are incorporated in predictive algorithms for fracture predisposition. FRAX (Fracture Risk Assessment) is a widely used screening tool that is valid in offering fracture risk quantification across populations (Arch Osteoporos. 2016 Dec;11[1]:25; World Health Organization Assessment of Osteoporosis at the Primary Health Care Level).
Aging and accompanying neurocognitive deterioration, visual impairment, as well as iatrogenic factors are recognized to contribute to predisposition to falls in aging populations. A propensity for falls has long been regarded as a fracture risk (Curr Osteoporos Rep. 2008;6[4]:149-54). However, the evidence to support this logical assumption has been mixed with resulting exclusion of tendency to fall from commonly utilized fracture risk predictive models and tools. A predisposition to and frequency of falls is considered neither a risk modulator nor a mediator in the commonly utilized FRAX-based fracture risk assessments, and it is believed that fracture probability may be underestimated by FRAX in those predisposed to frequent falls (J Clin Densitom. 2011 Jul-Sep;14[3]:194–204).
The landscape of fracture risk assessment and quantification in the aforementioned backdrop has been refreshingly enhanced by a recent contribution by Leslie et al. wherein the authors provide real-life evidence relating self-reported falls to fracture risk. In a robust population sample nearing 25,000 women, increasing number of falls within the past year was associated with an increasing fracture risk, and this relationship persisted after adjusting for covariates that are recognized to predispose to fragility fractures, including age, body mass index, and bone mineral density. Women’s health providers are encouraged to familiarize themselves with the work of Leslie et al.; the authors’ message, that fall history be incorporated into risk quantification measures, is striking in its simplicity and profound in its preventative potential given that fall risk in and of itself may be mitigated in many through targeted interventions.
Lubna Pal, MBBS, MS, is professor and fellowship director of the division of reproductive endocrinology & infertility at Yale University, New Haven, Conn. She also is the director of the Yale reproductive endocrinology & infertility menopause program. She said she had no relevant financial disclosures. Email her at [email protected].
A single, simple question about a patient’s experience of falls in the previous year can help predict their risk of fractures, a study suggests.
In Osteoporosis International, researchers reported the outcomes of a cohort study using Manitoba clinical registry data from 24,943 men and women aged 40 years and older within the province who had undergone a fracture-probability assessment, and had data on self-reported falls for the previous year and fracture outcomes.
William D. Leslie, MD, of the University of Manitoba in Winnipeg, and coauthors wrote that a frequent criticism of the FRAX fracture risk assessment tool was the fact that it didn’t include falls or fall risk in predicting fractures.
“Recent evidence derived from carefully conducted research cohort studies in men found that falls increase fracture risk independent of FRAX probability,” they wrote. “However, data are inconsistent with a paucity of evidence demonstrating usefulness of self-reported fall data as collected in routine clinical practice.”
0.8% experienced a hip fracture, and 4.9% experienced any incident fracture.
The analysis showed an increased risk of fracture with the increasing number of self-reported falls experienced in the previous year. The risk of major osteoporotic fracture was 49% higher among individuals who reported one fall, 74% in those who reported two falls and 2.6-fold higher for those who reported three or more falls in the previous year, compared with those who did not report any falls.
A similar pattern was seen for any incident fracture and hip fracture, with a 3.4-fold higher risk of hip fracture seen in those who reported three or more falls. The study also showed an increase in mortality risk with increasing number of falls.
“We documented that a simple question regarding self-reported falls in the previous year could be easily collected during routine clinical practice and that this information was strongly predictive of short-term fracture risk independent of multiple clinical risk factors including fracture probability using the FRAX tool with BMD [bone mineral density],” the authors wrote.
The analysis did not find an interaction with age or sex and the number of falls.
John A. Kanis, MD, reported grants from Amgen, Lily, and Radius Health. Three other coauthors reported nothing to declare for the context of this article, but reported research grants, speaking honoraria, consultancies from a variety of pharmaceutical companies and organizations. The remaining five coauthors declared no conflicts of interest.
SOURCE: Leslie WD et al. Osteoporos Int. 2019 Aug. 2. doi: 10.1007/s00198-019-05106-3.
A single, simple question about a patient’s experience of falls in the previous year can help predict their risk of fractures, a study suggests.
In Osteoporosis International, researchers reported the outcomes of a cohort study using Manitoba clinical registry data from 24,943 men and women aged 40 years and older within the province who had undergone a fracture-probability assessment, and had data on self-reported falls for the previous year and fracture outcomes.
William D. Leslie, MD, of the University of Manitoba in Winnipeg, and coauthors wrote that a frequent criticism of the FRAX fracture risk assessment tool was the fact that it didn’t include falls or fall risk in predicting fractures.
“Recent evidence derived from carefully conducted research cohort studies in men found that falls increase fracture risk independent of FRAX probability,” they wrote. “However, data are inconsistent with a paucity of evidence demonstrating usefulness of self-reported fall data as collected in routine clinical practice.”
0.8% experienced a hip fracture, and 4.9% experienced any incident fracture.
The analysis showed an increased risk of fracture with the increasing number of self-reported falls experienced in the previous year. The risk of major osteoporotic fracture was 49% higher among individuals who reported one fall, 74% in those who reported two falls and 2.6-fold higher for those who reported three or more falls in the previous year, compared with those who did not report any falls.
A similar pattern was seen for any incident fracture and hip fracture, with a 3.4-fold higher risk of hip fracture seen in those who reported three or more falls. The study also showed an increase in mortality risk with increasing number of falls.
“We documented that a simple question regarding self-reported falls in the previous year could be easily collected during routine clinical practice and that this information was strongly predictive of short-term fracture risk independent of multiple clinical risk factors including fracture probability using the FRAX tool with BMD [bone mineral density],” the authors wrote.
The analysis did not find an interaction with age or sex and the number of falls.
John A. Kanis, MD, reported grants from Amgen, Lily, and Radius Health. Three other coauthors reported nothing to declare for the context of this article, but reported research grants, speaking honoraria, consultancies from a variety of pharmaceutical companies and organizations. The remaining five coauthors declared no conflicts of interest.
SOURCE: Leslie WD et al. Osteoporos Int. 2019 Aug. 2. doi: 10.1007/s00198-019-05106-3.
FROM OSTEOPOROSIS INTERNATIONAL
Analysis finds no mortality reductions with osteoporosis drugs
A paper published in JAMA Internal Medicine analyzed data from 38 randomized, placebo-controlled clinical trials of osteoporosis drugs involving a total of 101,642 participants.
“Studies have estimated that less than 30% of the mortality following hip and vertebral fractures may be attributed to the fracture itself and, therefore, potentially avoidable by preventing the fracture,” wrote Steven R. Cummings, MD, of the San Francisco Coordinating Center at the University of California, San Francisco, and colleagues. “Some studies have suggested that treatments for osteoporosis may directly reduce overall mortality rates in addition to decreasing fracture risk.”
Despite including a diversity of drugs including bisphosphonates, denosumab (Prolia), selective estrogen receptor modulators, parathyroid hormone analogues, odanacatib, and romosozumab (Evenity), the analysis found no significant association between receiving a drug treatment for osteoporosis and overall mortality.
The researchers did a separate analysis of the 21 clinical trials of bisphosphonate treatments, again finding no impact of the treatment on overall mortality. Similarly, analysis of six zoledronate clinical trials found no statistically significant impact on mortality, although the authors noted that there was some heterogeneity in the results. For example, two large trials found 28% and 35% reductions in mortality, however these effects were not seen in another other zoledronate trials.
An analysis limited to nitrogen-containing bisphosphonates (alendronate, risedronate, ibandronate, and zoledronate) showed a nonsignificant trend toward lower overall mortality, although this became even less statistically significant when trials of zoledronate were excluded.
“More data from placebo-controlled clinical trials of zoledronate therapy and mortality rates are needed to resolve whether treatment with zoledronate is associated with reduced mortality in addition to decreased fracture risk,” the authors wrote.
They added that the 25%-60% mortality reductions seen in previous observational were too large to be attributable solely to reductions in the risk of fracture, but were perhaps the result of unmeasured confounders that could have contributed to lower mortality.
“The apparent reduction in mortality may be an example of the ‘healthy adherer effect,’ which has been documented in studies reporting that participants who adhered to placebo treatment in clinical trials had lower mortality,” they wrote, citing data from the Women’s Health Study that showed 36% lower mortality in those who were at least 80% adherent to placebo.
“This effect is particularly applicable to observational studies of treatments for osteoporosis because only an estimated half of women taking oral drugs for the treatment of osteoporosis continued the regimen for 1 year, and even fewer continued longer,” they added.
They did note one limitation of their analysis was that it did not include a large clinical trial of the antiresorptive drug odanacatib, which was only available in abstract form at the time.
One author reported receiving grants and personal fees from a pharmaceutical company during the conduct of the study, and another reported receiving grants and personal fees outside the submitted work. No other conflicts of interest were reported.
SOURCE: Cummings SR et al. JAMA Intern Med. 2019 Aug 19. doi: 10.1001/jamainternmed.2019.2779.
A paper published in JAMA Internal Medicine analyzed data from 38 randomized, placebo-controlled clinical trials of osteoporosis drugs involving a total of 101,642 participants.
“Studies have estimated that less than 30% of the mortality following hip and vertebral fractures may be attributed to the fracture itself and, therefore, potentially avoidable by preventing the fracture,” wrote Steven R. Cummings, MD, of the San Francisco Coordinating Center at the University of California, San Francisco, and colleagues. “Some studies have suggested that treatments for osteoporosis may directly reduce overall mortality rates in addition to decreasing fracture risk.”
Despite including a diversity of drugs including bisphosphonates, denosumab (Prolia), selective estrogen receptor modulators, parathyroid hormone analogues, odanacatib, and romosozumab (Evenity), the analysis found no significant association between receiving a drug treatment for osteoporosis and overall mortality.
The researchers did a separate analysis of the 21 clinical trials of bisphosphonate treatments, again finding no impact of the treatment on overall mortality. Similarly, analysis of six zoledronate clinical trials found no statistically significant impact on mortality, although the authors noted that there was some heterogeneity in the results. For example, two large trials found 28% and 35% reductions in mortality, however these effects were not seen in another other zoledronate trials.
An analysis limited to nitrogen-containing bisphosphonates (alendronate, risedronate, ibandronate, and zoledronate) showed a nonsignificant trend toward lower overall mortality, although this became even less statistically significant when trials of zoledronate were excluded.
“More data from placebo-controlled clinical trials of zoledronate therapy and mortality rates are needed to resolve whether treatment with zoledronate is associated with reduced mortality in addition to decreased fracture risk,” the authors wrote.
They added that the 25%-60% mortality reductions seen in previous observational were too large to be attributable solely to reductions in the risk of fracture, but were perhaps the result of unmeasured confounders that could have contributed to lower mortality.
“The apparent reduction in mortality may be an example of the ‘healthy adherer effect,’ which has been documented in studies reporting that participants who adhered to placebo treatment in clinical trials had lower mortality,” they wrote, citing data from the Women’s Health Study that showed 36% lower mortality in those who were at least 80% adherent to placebo.
“This effect is particularly applicable to observational studies of treatments for osteoporosis because only an estimated half of women taking oral drugs for the treatment of osteoporosis continued the regimen for 1 year, and even fewer continued longer,” they added.
They did note one limitation of their analysis was that it did not include a large clinical trial of the antiresorptive drug odanacatib, which was only available in abstract form at the time.
One author reported receiving grants and personal fees from a pharmaceutical company during the conduct of the study, and another reported receiving grants and personal fees outside the submitted work. No other conflicts of interest were reported.
SOURCE: Cummings SR et al. JAMA Intern Med. 2019 Aug 19. doi: 10.1001/jamainternmed.2019.2779.
A paper published in JAMA Internal Medicine analyzed data from 38 randomized, placebo-controlled clinical trials of osteoporosis drugs involving a total of 101,642 participants.
“Studies have estimated that less than 30% of the mortality following hip and vertebral fractures may be attributed to the fracture itself and, therefore, potentially avoidable by preventing the fracture,” wrote Steven R. Cummings, MD, of the San Francisco Coordinating Center at the University of California, San Francisco, and colleagues. “Some studies have suggested that treatments for osteoporosis may directly reduce overall mortality rates in addition to decreasing fracture risk.”
Despite including a diversity of drugs including bisphosphonates, denosumab (Prolia), selective estrogen receptor modulators, parathyroid hormone analogues, odanacatib, and romosozumab (Evenity), the analysis found no significant association between receiving a drug treatment for osteoporosis and overall mortality.
The researchers did a separate analysis of the 21 clinical trials of bisphosphonate treatments, again finding no impact of the treatment on overall mortality. Similarly, analysis of six zoledronate clinical trials found no statistically significant impact on mortality, although the authors noted that there was some heterogeneity in the results. For example, two large trials found 28% and 35% reductions in mortality, however these effects were not seen in another other zoledronate trials.
An analysis limited to nitrogen-containing bisphosphonates (alendronate, risedronate, ibandronate, and zoledronate) showed a nonsignificant trend toward lower overall mortality, although this became even less statistically significant when trials of zoledronate were excluded.
“More data from placebo-controlled clinical trials of zoledronate therapy and mortality rates are needed to resolve whether treatment with zoledronate is associated with reduced mortality in addition to decreased fracture risk,” the authors wrote.
They added that the 25%-60% mortality reductions seen in previous observational were too large to be attributable solely to reductions in the risk of fracture, but were perhaps the result of unmeasured confounders that could have contributed to lower mortality.
“The apparent reduction in mortality may be an example of the ‘healthy adherer effect,’ which has been documented in studies reporting that participants who adhered to placebo treatment in clinical trials had lower mortality,” they wrote, citing data from the Women’s Health Study that showed 36% lower mortality in those who were at least 80% adherent to placebo.
“This effect is particularly applicable to observational studies of treatments for osteoporosis because only an estimated half of women taking oral drugs for the treatment of osteoporosis continued the regimen for 1 year, and even fewer continued longer,” they added.
They did note one limitation of their analysis was that it did not include a large clinical trial of the antiresorptive drug odanacatib, which was only available in abstract form at the time.
One author reported receiving grants and personal fees from a pharmaceutical company during the conduct of the study, and another reported receiving grants and personal fees outside the submitted work. No other conflicts of interest were reported.
SOURCE: Cummings SR et al. JAMA Intern Med. 2019 Aug 19. doi: 10.1001/jamainternmed.2019.2779.
FROM JAMA INTERNAL MEDICINE
Consider hormones and mood in adolescent girls
Prior to puberty, the rate of mood disorders in males and females is roughly the same; however in adolescence, depression doubles in (biological) girls. While the association isn’t clear, it is reasonable to consider that hormones may be involved, at least for some. For instance, we know that menstrual cycle–related mood changes have been noted since the time of Hippocrates. In this article, I will discuss premenstrual dysphoric disorder (PMDD), as well as potential mood-related side effects of hormonal contraceptives. Because I am talking about physiology, I will be referring to individuals born as biological females in the absence of any hormonal gender treatments, regardless of identified gender.
Many young women will acknowledge somatic and/or psychological symptoms that occur in the luteal phase of their cycle, most commonly in the week before menses begins. The most common somatic symptom is bloating, and mood symptoms are irritability and mood lability.1 To meet criteria for premenstrual syndrome (PMS), a woman must endorse one symptom that causes impairment in their functioning and reoccurs over consecutive cycles. PMDD is more specific and involves five or more affective symptoms, at least one of which is consistent with depressed mood, irritability, anxiety, or mood lability. The other potential symptoms include impaired concentration, fatigue, insomnia or hypersomnia, anhedonia, and appetite issues, all of which are included as criteria for major depression. The population prevalence has been quoted between 2% and 5% and is relatively stable across cultures.1 It tends to be highly genetic, as well as highly comorbid with other psychiatric disorders.2 Girls and women with higher rates of trauma appear to be more likely to experience symptoms,3 which indicates there are environmental influences that can interact with genetic vulnerability.
Interestingly, studies have not found differences in serum hormone levels between those with PMDD and others, which leads to the hypothesis that the main difference is in a woman’s sensitivity to circulating hormones,4 and there has been some evidence of different concentrations of neurotransmitters between affected and unaffected women. Many hormone-neurotransmitter interactions have been described, but two that have received the most attention include the relationship between progesterone, its main metabolite allopregnanolone, and gamma-aminobutyric acid (GABA) receptors. Allopregnanolone, which interacts with GABA receptors similarly to benzodiazepines, tends to be higher in the luteal phase, rising with progesterone, and the concentration quickly recedes at the onset of menses as progesterone levels drop off. The other highly notable relationship is the positive association between estradiol and the expression of the serotonin transporter (SERT) genes, which can potentially lead to higher levels of circulating serotonin in the follicular phase.
When PMDD is suspected in an adolescent who presents with intermittent mood and anxiety symptoms that lessen or disappear at baseline and appear unrelated to circumstances, it is important to check in regarding monthly patterns. It can be challenging for adolescents to make this connection, and even more so prior to achieving cycle regularity. Observational studies suggest that by age 14 years, about 82% of girls have a regular cycle.5 The best way to help a patient make the connection is to suggest a period tracking app on their smartphone or tablet. There are many available period trackers that track mood as well and are free to download. Sometimes, simply the act of tracking and bringing awareness to the pattern is therapeutic in itself; sometimes, more formal treatment is needed.
Once the diagnosis of PMDD has been established, there are several options for treatment that range from supplements and herbal remedies to SSRIs, as well as psychotherapy. Treatment may begin with calcium supplements (1,200 mg have been effective in reducing symptoms)6 and referral for cognitive-behavioral therapy (CBT). CBT appears to be associated with a shift in the ability to attribute symptoms to hormones,7 which can help decrease hopelessness and reactivity. SSRIs are another effective strategy to treat PMDD, both taken daily and continuously and also taken in a pulsed fashion, starting with the onset of symptoms or 7-10 days before the period starts and stopping on the first day of menses. Low doses of sertraline, fluoxetine, paroxetine, escitalopram and citalopram have been studied.8 There is some low-quality evidence for herbal supplements as well, probably the most consistent finding is for Vitex taken the week prior to menses.9 Finally, certain oral contraceptives have been associated with PMDD symptom reduction, specifically formulations with 3 mg of drospirenone (a fourth generation progesterone) and 20 mcg of ethinyl estradiol.10 Other formulations, including progesterone-only pills, have not been helpful and have been demonstrated to have a negative effect on mood.11
The literature on hormonal contraceptives and mood can be confusing. While oral agents containing drospirenone have been helpful for premenstrual dysphoria, other studies outside of the PMDD literature have found positive associations between oral contraceptives and depression in adolescents.11 Girls taking combined oral contraceptives seem to be at a 1.8-fold risk of depression, while girls taking progesterone-only formulations were at 2.2 times the risk of developing depression, compared with girls who weren’t taking anything. These days, more pediatricians are recommending long acting reversible contraceptives (LARCs), and there is some thought that even these may carry some risk, but this remains to be studied.
In conclusion, As a provider, you are in a special position to help your patients by bringing nonjudgmental awareness to the potential contribution of their own cyclical hormones or that of exogenous hormones associated with contraceptive choices. Whether it means switching contraceptives, adding calcium or starting a low dose SSRI for 1 week a month, there are many ways to approach symptoms. Often, simply helping make the connection between physiology and mood can be empowering.
Dr. Guth is an assistant professor in the department of psychiatry at the University of Vermont Medical Center and the University of Vermont, both in Burlington. Email her at [email protected].
References
1. Am J Psychiatry. 2012 May;169(5):465-75.
2. Arch Womens Ment Health. 2004 Feb;7(1):37-47.
3. Arch Womens Ment Health. 2011 Oct;14(5):383-93.
4. Curr Psychiatry Rep. 2015 Nov;17(11):87.
5. Ital J Pediatr. 2012 Aug 14;38:38.
6. Am J Obstet Gynecol. 1998 Aug;179(2):444-52.
7. J Clin Psychol Med Settings. 2012 Sep;19(3):308-19.
8. Cochrane Database Syst Rev. 2013 Jun 7;(6):CD001396.
9. J Psychosom Obstet Gynaecol. 2011 Mar;32(1):42-51.
10. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD006586.
11. PLoS One. 2018 Mar 22;13(3):e0194773.
Prior to puberty, the rate of mood disorders in males and females is roughly the same; however in adolescence, depression doubles in (biological) girls. While the association isn’t clear, it is reasonable to consider that hormones may be involved, at least for some. For instance, we know that menstrual cycle–related mood changes have been noted since the time of Hippocrates. In this article, I will discuss premenstrual dysphoric disorder (PMDD), as well as potential mood-related side effects of hormonal contraceptives. Because I am talking about physiology, I will be referring to individuals born as biological females in the absence of any hormonal gender treatments, regardless of identified gender.
Many young women will acknowledge somatic and/or psychological symptoms that occur in the luteal phase of their cycle, most commonly in the week before menses begins. The most common somatic symptom is bloating, and mood symptoms are irritability and mood lability.1 To meet criteria for premenstrual syndrome (PMS), a woman must endorse one symptom that causes impairment in their functioning and reoccurs over consecutive cycles. PMDD is more specific and involves five or more affective symptoms, at least one of which is consistent with depressed mood, irritability, anxiety, or mood lability. The other potential symptoms include impaired concentration, fatigue, insomnia or hypersomnia, anhedonia, and appetite issues, all of which are included as criteria for major depression. The population prevalence has been quoted between 2% and 5% and is relatively stable across cultures.1 It tends to be highly genetic, as well as highly comorbid with other psychiatric disorders.2 Girls and women with higher rates of trauma appear to be more likely to experience symptoms,3 which indicates there are environmental influences that can interact with genetic vulnerability.
Interestingly, studies have not found differences in serum hormone levels between those with PMDD and others, which leads to the hypothesis that the main difference is in a woman’s sensitivity to circulating hormones,4 and there has been some evidence of different concentrations of neurotransmitters between affected and unaffected women. Many hormone-neurotransmitter interactions have been described, but two that have received the most attention include the relationship between progesterone, its main metabolite allopregnanolone, and gamma-aminobutyric acid (GABA) receptors. Allopregnanolone, which interacts with GABA receptors similarly to benzodiazepines, tends to be higher in the luteal phase, rising with progesterone, and the concentration quickly recedes at the onset of menses as progesterone levels drop off. The other highly notable relationship is the positive association between estradiol and the expression of the serotonin transporter (SERT) genes, which can potentially lead to higher levels of circulating serotonin in the follicular phase.
When PMDD is suspected in an adolescent who presents with intermittent mood and anxiety symptoms that lessen or disappear at baseline and appear unrelated to circumstances, it is important to check in regarding monthly patterns. It can be challenging for adolescents to make this connection, and even more so prior to achieving cycle regularity. Observational studies suggest that by age 14 years, about 82% of girls have a regular cycle.5 The best way to help a patient make the connection is to suggest a period tracking app on their smartphone or tablet. There are many available period trackers that track mood as well and are free to download. Sometimes, simply the act of tracking and bringing awareness to the pattern is therapeutic in itself; sometimes, more formal treatment is needed.
Once the diagnosis of PMDD has been established, there are several options for treatment that range from supplements and herbal remedies to SSRIs, as well as psychotherapy. Treatment may begin with calcium supplements (1,200 mg have been effective in reducing symptoms)6 and referral for cognitive-behavioral therapy (CBT). CBT appears to be associated with a shift in the ability to attribute symptoms to hormones,7 which can help decrease hopelessness and reactivity. SSRIs are another effective strategy to treat PMDD, both taken daily and continuously and also taken in a pulsed fashion, starting with the onset of symptoms or 7-10 days before the period starts and stopping on the first day of menses. Low doses of sertraline, fluoxetine, paroxetine, escitalopram and citalopram have been studied.8 There is some low-quality evidence for herbal supplements as well, probably the most consistent finding is for Vitex taken the week prior to menses.9 Finally, certain oral contraceptives have been associated with PMDD symptom reduction, specifically formulations with 3 mg of drospirenone (a fourth generation progesterone) and 20 mcg of ethinyl estradiol.10 Other formulations, including progesterone-only pills, have not been helpful and have been demonstrated to have a negative effect on mood.11
The literature on hormonal contraceptives and mood can be confusing. While oral agents containing drospirenone have been helpful for premenstrual dysphoria, other studies outside of the PMDD literature have found positive associations between oral contraceptives and depression in adolescents.11 Girls taking combined oral contraceptives seem to be at a 1.8-fold risk of depression, while girls taking progesterone-only formulations were at 2.2 times the risk of developing depression, compared with girls who weren’t taking anything. These days, more pediatricians are recommending long acting reversible contraceptives (LARCs), and there is some thought that even these may carry some risk, but this remains to be studied.
In conclusion, As a provider, you are in a special position to help your patients by bringing nonjudgmental awareness to the potential contribution of their own cyclical hormones or that of exogenous hormones associated with contraceptive choices. Whether it means switching contraceptives, adding calcium or starting a low dose SSRI for 1 week a month, there are many ways to approach symptoms. Often, simply helping make the connection between physiology and mood can be empowering.
Dr. Guth is an assistant professor in the department of psychiatry at the University of Vermont Medical Center and the University of Vermont, both in Burlington. Email her at [email protected].
References
1. Am J Psychiatry. 2012 May;169(5):465-75.
2. Arch Womens Ment Health. 2004 Feb;7(1):37-47.
3. Arch Womens Ment Health. 2011 Oct;14(5):383-93.
4. Curr Psychiatry Rep. 2015 Nov;17(11):87.
5. Ital J Pediatr. 2012 Aug 14;38:38.
6. Am J Obstet Gynecol. 1998 Aug;179(2):444-52.
7. J Clin Psychol Med Settings. 2012 Sep;19(3):308-19.
8. Cochrane Database Syst Rev. 2013 Jun 7;(6):CD001396.
9. J Psychosom Obstet Gynaecol. 2011 Mar;32(1):42-51.
10. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD006586.
11. PLoS One. 2018 Mar 22;13(3):e0194773.
Prior to puberty, the rate of mood disorders in males and females is roughly the same; however in adolescence, depression doubles in (biological) girls. While the association isn’t clear, it is reasonable to consider that hormones may be involved, at least for some. For instance, we know that menstrual cycle–related mood changes have been noted since the time of Hippocrates. In this article, I will discuss premenstrual dysphoric disorder (PMDD), as well as potential mood-related side effects of hormonal contraceptives. Because I am talking about physiology, I will be referring to individuals born as biological females in the absence of any hormonal gender treatments, regardless of identified gender.
Many young women will acknowledge somatic and/or psychological symptoms that occur in the luteal phase of their cycle, most commonly in the week before menses begins. The most common somatic symptom is bloating, and mood symptoms are irritability and mood lability.1 To meet criteria for premenstrual syndrome (PMS), a woman must endorse one symptom that causes impairment in their functioning and reoccurs over consecutive cycles. PMDD is more specific and involves five or more affective symptoms, at least one of which is consistent with depressed mood, irritability, anxiety, or mood lability. The other potential symptoms include impaired concentration, fatigue, insomnia or hypersomnia, anhedonia, and appetite issues, all of which are included as criteria for major depression. The population prevalence has been quoted between 2% and 5% and is relatively stable across cultures.1 It tends to be highly genetic, as well as highly comorbid with other psychiatric disorders.2 Girls and women with higher rates of trauma appear to be more likely to experience symptoms,3 which indicates there are environmental influences that can interact with genetic vulnerability.
Interestingly, studies have not found differences in serum hormone levels between those with PMDD and others, which leads to the hypothesis that the main difference is in a woman’s sensitivity to circulating hormones,4 and there has been some evidence of different concentrations of neurotransmitters between affected and unaffected women. Many hormone-neurotransmitter interactions have been described, but two that have received the most attention include the relationship between progesterone, its main metabolite allopregnanolone, and gamma-aminobutyric acid (GABA) receptors. Allopregnanolone, which interacts with GABA receptors similarly to benzodiazepines, tends to be higher in the luteal phase, rising with progesterone, and the concentration quickly recedes at the onset of menses as progesterone levels drop off. The other highly notable relationship is the positive association between estradiol and the expression of the serotonin transporter (SERT) genes, which can potentially lead to higher levels of circulating serotonin in the follicular phase.
When PMDD is suspected in an adolescent who presents with intermittent mood and anxiety symptoms that lessen or disappear at baseline and appear unrelated to circumstances, it is important to check in regarding monthly patterns. It can be challenging for adolescents to make this connection, and even more so prior to achieving cycle regularity. Observational studies suggest that by age 14 years, about 82% of girls have a regular cycle.5 The best way to help a patient make the connection is to suggest a period tracking app on their smartphone or tablet. There are many available period trackers that track mood as well and are free to download. Sometimes, simply the act of tracking and bringing awareness to the pattern is therapeutic in itself; sometimes, more formal treatment is needed.
Once the diagnosis of PMDD has been established, there are several options for treatment that range from supplements and herbal remedies to SSRIs, as well as psychotherapy. Treatment may begin with calcium supplements (1,200 mg have been effective in reducing symptoms)6 and referral for cognitive-behavioral therapy (CBT). CBT appears to be associated with a shift in the ability to attribute symptoms to hormones,7 which can help decrease hopelessness and reactivity. SSRIs are another effective strategy to treat PMDD, both taken daily and continuously and also taken in a pulsed fashion, starting with the onset of symptoms or 7-10 days before the period starts and stopping on the first day of menses. Low doses of sertraline, fluoxetine, paroxetine, escitalopram and citalopram have been studied.8 There is some low-quality evidence for herbal supplements as well, probably the most consistent finding is for Vitex taken the week prior to menses.9 Finally, certain oral contraceptives have been associated with PMDD symptom reduction, specifically formulations with 3 mg of drospirenone (a fourth generation progesterone) and 20 mcg of ethinyl estradiol.10 Other formulations, including progesterone-only pills, have not been helpful and have been demonstrated to have a negative effect on mood.11
The literature on hormonal contraceptives and mood can be confusing. While oral agents containing drospirenone have been helpful for premenstrual dysphoria, other studies outside of the PMDD literature have found positive associations between oral contraceptives and depression in adolescents.11 Girls taking combined oral contraceptives seem to be at a 1.8-fold risk of depression, while girls taking progesterone-only formulations were at 2.2 times the risk of developing depression, compared with girls who weren’t taking anything. These days, more pediatricians are recommending long acting reversible contraceptives (LARCs), and there is some thought that even these may carry some risk, but this remains to be studied.
In conclusion, As a provider, you are in a special position to help your patients by bringing nonjudgmental awareness to the potential contribution of their own cyclical hormones or that of exogenous hormones associated with contraceptive choices. Whether it means switching contraceptives, adding calcium or starting a low dose SSRI for 1 week a month, there are many ways to approach symptoms. Often, simply helping make the connection between physiology and mood can be empowering.
Dr. Guth is an assistant professor in the department of psychiatry at the University of Vermont Medical Center and the University of Vermont, both in Burlington. Email her at [email protected].
References
1. Am J Psychiatry. 2012 May;169(5):465-75.
2. Arch Womens Ment Health. 2004 Feb;7(1):37-47.
3. Arch Womens Ment Health. 2011 Oct;14(5):383-93.
4. Curr Psychiatry Rep. 2015 Nov;17(11):87.
5. Ital J Pediatr. 2012 Aug 14;38:38.
6. Am J Obstet Gynecol. 1998 Aug;179(2):444-52.
7. J Clin Psychol Med Settings. 2012 Sep;19(3):308-19.
8. Cochrane Database Syst Rev. 2013 Jun 7;(6):CD001396.
9. J Psychosom Obstet Gynaecol. 2011 Mar;32(1):42-51.
10. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD006586.
11. PLoS One. 2018 Mar 22;13(3):e0194773.
Bisphosphonates improve BMD in pediatric rheumatic disease
Prophylactic treatment with bisphosphonates could significantly improve bone mineral density (BMD) in children and adolescents receiving steroids for chronic rheumatic disease, a study has found.
A paper published in EClinicalMedicine reported the outcomes of a multicenter, double-dummy, double-blind, placebo-controlled trial involving 217 patients who were receiving steroid therapy for juvenile idiopathic arthritis, juvenile systemic lupus erythematosus, juvenile dermatomyositis, or juvenile vasculitis. The patients were randomized to risedronate, alfacalcidol, or placebo, and all of the participants received 500 mg calcium and 400 IU vitamin D daily.
Lumbar spine and total body (less head) BMD increased in all groups, but the greatest increase was seen in patients treated with risedronate.
After 1 year, lumbar spine and total body (less head) BMD had increased in all groups, compared with baseline, but the greatest increase was seen in patients who had been treated with risedronate.
The lumbar spine areal BMD z score remained the same in the placebo group (−1.15 to −1.13), decreased from −0.96 to −1.00 in the alfacalcidol group, and increased from −0.99 to −0.75 in the risedronate group.
The change in z scores was significantly different between placebo and risedronate groups, and between risedronate and alfacalcidol groups, but not between placebo and alfacalcidol.
“The acquisition of adequate peak bone mass is not only important for the young person in reducing fracture risk but also has significant implications for the development of osteoporosis in later life, if peak bone mass is suboptimal,” wrote Madeleine Rooney, MBBCH, from the Queens University of Belfast, Northern Ireland, and associates.
There were no significant differences between the three groups in fracture rates. However, researchers were also able to compare Genant scores for vertebral fractures in 187 patients with pre- and posttreatment lateral spinal x-rays. That showed that the 54 patients in the placebo arm and 52 patients in the alfacalcidol arm had no change in their baseline Genant score of 0 (normal). However, although all 53 patients in the risedronate group had a Genant score of 0 at baseline, at 1-year follow-up, 2 patients had a Genant score of 1 (mild fracture), and 1 patient had a score of 3 (severe fracture).
In biochemical parameters, researchers saw a drop in parathyroid hormone in the placebo and alfacalcidol groups, but a rise in the risedronate group. However, the authors were not able to see any changes in bone markers that might have indicated which patients responded better to treatment.
Around 90% of participants in each group were also being treated with disease-modifying antirheumatic drugs. The rates of biologic use were 10.5% in the placebo group, 23.9% in the alfacalcidol group, and 10.1% in the risedronate group.
The researchers also noted a 7% higher rate of serious adverse events in the risedronate group, but emphasized that there were no differences in events related to the treatment.
In an accompanying editorial, Ian R. Reid, MBBCH, of the department of medicine, University of Auckland (New Zealand) noted that the study was an important step toward finding interventions for the prevention of steroid-induced bone loss in children. “The present study indicates that risedronate, and probably other potent bisphosphonates, can provide bone preservation in children and young people receiving therapeutic doses of glucocorticoid drugs, whereas alfacalcidol is without benefit. The targeted use of bisphosphonates in children and young people judged to be at significant fracture risk is appropriate. However, whether preventing loss of bone density will reduce fracture incidence remains to be established.”
The study was funded by Arthritis Research UK. No conflicts of interest were declared.
SOURCE: Rooney M et al. EClinicalMedicine. 2019 Jul 3. doi: 10.1016/j.eclinm.2019.06.004.
Prophylactic treatment with bisphosphonates could significantly improve bone mineral density (BMD) in children and adolescents receiving steroids for chronic rheumatic disease, a study has found.
A paper published in EClinicalMedicine reported the outcomes of a multicenter, double-dummy, double-blind, placebo-controlled trial involving 217 patients who were receiving steroid therapy for juvenile idiopathic arthritis, juvenile systemic lupus erythematosus, juvenile dermatomyositis, or juvenile vasculitis. The patients were randomized to risedronate, alfacalcidol, or placebo, and all of the participants received 500 mg calcium and 400 IU vitamin D daily.
Lumbar spine and total body (less head) BMD increased in all groups, but the greatest increase was seen in patients treated with risedronate.
After 1 year, lumbar spine and total body (less head) BMD had increased in all groups, compared with baseline, but the greatest increase was seen in patients who had been treated with risedronate.
The lumbar spine areal BMD z score remained the same in the placebo group (−1.15 to −1.13), decreased from −0.96 to −1.00 in the alfacalcidol group, and increased from −0.99 to −0.75 in the risedronate group.
The change in z scores was significantly different between placebo and risedronate groups, and between risedronate and alfacalcidol groups, but not between placebo and alfacalcidol.
“The acquisition of adequate peak bone mass is not only important for the young person in reducing fracture risk but also has significant implications for the development of osteoporosis in later life, if peak bone mass is suboptimal,” wrote Madeleine Rooney, MBBCH, from the Queens University of Belfast, Northern Ireland, and associates.
There were no significant differences between the three groups in fracture rates. However, researchers were also able to compare Genant scores for vertebral fractures in 187 patients with pre- and posttreatment lateral spinal x-rays. That showed that the 54 patients in the placebo arm and 52 patients in the alfacalcidol arm had no change in their baseline Genant score of 0 (normal). However, although all 53 patients in the risedronate group had a Genant score of 0 at baseline, at 1-year follow-up, 2 patients had a Genant score of 1 (mild fracture), and 1 patient had a score of 3 (severe fracture).
In biochemical parameters, researchers saw a drop in parathyroid hormone in the placebo and alfacalcidol groups, but a rise in the risedronate group. However, the authors were not able to see any changes in bone markers that might have indicated which patients responded better to treatment.
Around 90% of participants in each group were also being treated with disease-modifying antirheumatic drugs. The rates of biologic use were 10.5% in the placebo group, 23.9% in the alfacalcidol group, and 10.1% in the risedronate group.
The researchers also noted a 7% higher rate of serious adverse events in the risedronate group, but emphasized that there were no differences in events related to the treatment.
In an accompanying editorial, Ian R. Reid, MBBCH, of the department of medicine, University of Auckland (New Zealand) noted that the study was an important step toward finding interventions for the prevention of steroid-induced bone loss in children. “The present study indicates that risedronate, and probably other potent bisphosphonates, can provide bone preservation in children and young people receiving therapeutic doses of glucocorticoid drugs, whereas alfacalcidol is without benefit. The targeted use of bisphosphonates in children and young people judged to be at significant fracture risk is appropriate. However, whether preventing loss of bone density will reduce fracture incidence remains to be established.”
The study was funded by Arthritis Research UK. No conflicts of interest were declared.
SOURCE: Rooney M et al. EClinicalMedicine. 2019 Jul 3. doi: 10.1016/j.eclinm.2019.06.004.
Prophylactic treatment with bisphosphonates could significantly improve bone mineral density (BMD) in children and adolescents receiving steroids for chronic rheumatic disease, a study has found.
A paper published in EClinicalMedicine reported the outcomes of a multicenter, double-dummy, double-blind, placebo-controlled trial involving 217 patients who were receiving steroid therapy for juvenile idiopathic arthritis, juvenile systemic lupus erythematosus, juvenile dermatomyositis, or juvenile vasculitis. The patients were randomized to risedronate, alfacalcidol, or placebo, and all of the participants received 500 mg calcium and 400 IU vitamin D daily.
Lumbar spine and total body (less head) BMD increased in all groups, but the greatest increase was seen in patients treated with risedronate.
After 1 year, lumbar spine and total body (less head) BMD had increased in all groups, compared with baseline, but the greatest increase was seen in patients who had been treated with risedronate.
The lumbar spine areal BMD z score remained the same in the placebo group (−1.15 to −1.13), decreased from −0.96 to −1.00 in the alfacalcidol group, and increased from −0.99 to −0.75 in the risedronate group.
The change in z scores was significantly different between placebo and risedronate groups, and between risedronate and alfacalcidol groups, but not between placebo and alfacalcidol.
“The acquisition of adequate peak bone mass is not only important for the young person in reducing fracture risk but also has significant implications for the development of osteoporosis in later life, if peak bone mass is suboptimal,” wrote Madeleine Rooney, MBBCH, from the Queens University of Belfast, Northern Ireland, and associates.
There were no significant differences between the three groups in fracture rates. However, researchers were also able to compare Genant scores for vertebral fractures in 187 patients with pre- and posttreatment lateral spinal x-rays. That showed that the 54 patients in the placebo arm and 52 patients in the alfacalcidol arm had no change in their baseline Genant score of 0 (normal). However, although all 53 patients in the risedronate group had a Genant score of 0 at baseline, at 1-year follow-up, 2 patients had a Genant score of 1 (mild fracture), and 1 patient had a score of 3 (severe fracture).
In biochemical parameters, researchers saw a drop in parathyroid hormone in the placebo and alfacalcidol groups, but a rise in the risedronate group. However, the authors were not able to see any changes in bone markers that might have indicated which patients responded better to treatment.
Around 90% of participants in each group were also being treated with disease-modifying antirheumatic drugs. The rates of biologic use were 10.5% in the placebo group, 23.9% in the alfacalcidol group, and 10.1% in the risedronate group.
The researchers also noted a 7% higher rate of serious adverse events in the risedronate group, but emphasized that there were no differences in events related to the treatment.
In an accompanying editorial, Ian R. Reid, MBBCH, of the department of medicine, University of Auckland (New Zealand) noted that the study was an important step toward finding interventions for the prevention of steroid-induced bone loss in children. “The present study indicates that risedronate, and probably other potent bisphosphonates, can provide bone preservation in children and young people receiving therapeutic doses of glucocorticoid drugs, whereas alfacalcidol is without benefit. The targeted use of bisphosphonates in children and young people judged to be at significant fracture risk is appropriate. However, whether preventing loss of bone density will reduce fracture incidence remains to be established.”
The study was funded by Arthritis Research UK. No conflicts of interest were declared.
SOURCE: Rooney M et al. EClinicalMedicine. 2019 Jul 3. doi: 10.1016/j.eclinm.2019.06.004.
FROM ECLINICALMEDICINE
PCOS incidence is on the rise, but it remains underdiagnosed and undermanaged
SAN DIEGO – The incidence of polycystic ovary syndrome (PCOS) is on the rise, and a nurse practitioner urged her colleagues to give it full attention because of the danger it poses to patients.
“Underdiagnosed and undermanaged, it’s complex and a more serious condition than ever before because of the complications that can occur,” said R. Mimi Secor, DNP, FNP-BC, FAANP, FAAN, who spoke at the Metabolic & Endocrine Disease Summit by Global Academy for Medical Education.
PCOS is the most common reproductive endocrine disorder in the United States, affecting more than 5 million women, or an estimated 6%-10% of the population. Obesity is a risk factor, although lean women account for 10% of cases for reasons that are not understood, according to Dr. Secor, a senior lecturer at Advanced Practice Education Associates in Onset, Mass. In addition, the condition is linked to many sequelae, including multiple sclerosis, diabetes, cardiovascular disease, infertility, mental health problems, and cancer, she said.
Dr. Secor offered these pearls about PCOS:
- Understand the predictive value of oligomenorrhea (infrequent menstrual periods) as a sign of PCOS. “If you’re working in a low-income clinic, you can do well to make a diagnosis without a lot of expensive tests,” she said.
- Urge women with PCOS to get pregnant early if they want to have children. “Infertility is a big problem [among these women],” she said. “They shouldn’t wait until they’re 35 to have babies. They should have them in their 20s.”
- Use insulin control as a tool. “Insulin stimulates ovarian production of testosterone. If we can manage patients around insulin, that can be very helpful.” Losing just 5% of body weight can make a difference in insulin control, Dr. Secor said. “Go for a small change, and help [the patient] maintain that.”
- Monitor patients carefully for cancer. Women who don’t ovulate regularly on a monthly basis face a higher risk of uterine cancer, compared with women who ovulate monthly, she said, and tumors can develop with few symptoms. “If [there is] one drop of bleeding more than a year after menopause,” you need to get a mandatory workup to make sure the patient doesn’t have uterine cancer. Biopsy remains the “gold standard” as a diagnostic tool, she reminded attendees.
- Watch for mental health conditions, especially anxiety, in patients with PCOS. “They seem to be wired for anxiety, and they need a lot of emotional support,” Dr. Secor said.
- Hormonal contraceptives can be safe and effective as a treatment for PCOS in women who don’t wish to become pregnant, she said. But be aware that combination contraceptive drugs can affect women emotionally.
Global Academy and this news organization are owned by the same parent company. Dr. Secor disclosed speaker relationships with Duchesnay and Osphena.
SAN DIEGO – The incidence of polycystic ovary syndrome (PCOS) is on the rise, and a nurse practitioner urged her colleagues to give it full attention because of the danger it poses to patients.
“Underdiagnosed and undermanaged, it’s complex and a more serious condition than ever before because of the complications that can occur,” said R. Mimi Secor, DNP, FNP-BC, FAANP, FAAN, who spoke at the Metabolic & Endocrine Disease Summit by Global Academy for Medical Education.
PCOS is the most common reproductive endocrine disorder in the United States, affecting more than 5 million women, or an estimated 6%-10% of the population. Obesity is a risk factor, although lean women account for 10% of cases for reasons that are not understood, according to Dr. Secor, a senior lecturer at Advanced Practice Education Associates in Onset, Mass. In addition, the condition is linked to many sequelae, including multiple sclerosis, diabetes, cardiovascular disease, infertility, mental health problems, and cancer, she said.
Dr. Secor offered these pearls about PCOS:
- Understand the predictive value of oligomenorrhea (infrequent menstrual periods) as a sign of PCOS. “If you’re working in a low-income clinic, you can do well to make a diagnosis without a lot of expensive tests,” she said.
- Urge women with PCOS to get pregnant early if they want to have children. “Infertility is a big problem [among these women],” she said. “They shouldn’t wait until they’re 35 to have babies. They should have them in their 20s.”
- Use insulin control as a tool. “Insulin stimulates ovarian production of testosterone. If we can manage patients around insulin, that can be very helpful.” Losing just 5% of body weight can make a difference in insulin control, Dr. Secor said. “Go for a small change, and help [the patient] maintain that.”
- Monitor patients carefully for cancer. Women who don’t ovulate regularly on a monthly basis face a higher risk of uterine cancer, compared with women who ovulate monthly, she said, and tumors can develop with few symptoms. “If [there is] one drop of bleeding more than a year after menopause,” you need to get a mandatory workup to make sure the patient doesn’t have uterine cancer. Biopsy remains the “gold standard” as a diagnostic tool, she reminded attendees.
- Watch for mental health conditions, especially anxiety, in patients with PCOS. “They seem to be wired for anxiety, and they need a lot of emotional support,” Dr. Secor said.
- Hormonal contraceptives can be safe and effective as a treatment for PCOS in women who don’t wish to become pregnant, she said. But be aware that combination contraceptive drugs can affect women emotionally.
Global Academy and this news organization are owned by the same parent company. Dr. Secor disclosed speaker relationships with Duchesnay and Osphena.
SAN DIEGO – The incidence of polycystic ovary syndrome (PCOS) is on the rise, and a nurse practitioner urged her colleagues to give it full attention because of the danger it poses to patients.
“Underdiagnosed and undermanaged, it’s complex and a more serious condition than ever before because of the complications that can occur,” said R. Mimi Secor, DNP, FNP-BC, FAANP, FAAN, who spoke at the Metabolic & Endocrine Disease Summit by Global Academy for Medical Education.
PCOS is the most common reproductive endocrine disorder in the United States, affecting more than 5 million women, or an estimated 6%-10% of the population. Obesity is a risk factor, although lean women account for 10% of cases for reasons that are not understood, according to Dr. Secor, a senior lecturer at Advanced Practice Education Associates in Onset, Mass. In addition, the condition is linked to many sequelae, including multiple sclerosis, diabetes, cardiovascular disease, infertility, mental health problems, and cancer, she said.
Dr. Secor offered these pearls about PCOS:
- Understand the predictive value of oligomenorrhea (infrequent menstrual periods) as a sign of PCOS. “If you’re working in a low-income clinic, you can do well to make a diagnosis without a lot of expensive tests,” she said.
- Urge women with PCOS to get pregnant early if they want to have children. “Infertility is a big problem [among these women],” she said. “They shouldn’t wait until they’re 35 to have babies. They should have them in their 20s.”
- Use insulin control as a tool. “Insulin stimulates ovarian production of testosterone. If we can manage patients around insulin, that can be very helpful.” Losing just 5% of body weight can make a difference in insulin control, Dr. Secor said. “Go for a small change, and help [the patient] maintain that.”
- Monitor patients carefully for cancer. Women who don’t ovulate regularly on a monthly basis face a higher risk of uterine cancer, compared with women who ovulate monthly, she said, and tumors can develop with few symptoms. “If [there is] one drop of bleeding more than a year after menopause,” you need to get a mandatory workup to make sure the patient doesn’t have uterine cancer. Biopsy remains the “gold standard” as a diagnostic tool, she reminded attendees.
- Watch for mental health conditions, especially anxiety, in patients with PCOS. “They seem to be wired for anxiety, and they need a lot of emotional support,” Dr. Secor said.
- Hormonal contraceptives can be safe and effective as a treatment for PCOS in women who don’t wish to become pregnant, she said. But be aware that combination contraceptive drugs can affect women emotionally.
Global Academy and this news organization are owned by the same parent company. Dr. Secor disclosed speaker relationships with Duchesnay and Osphena.
REPORTING FROM MEDS 2019
Semen cryopreservation viable for young transgender patients in small study
as transgender women, according to results of a small retrospective cohort study.
The lack of data on this topic, however, makes it difficult to determine how long an individual must be off gender-affirming therapy before spermatogenesis resumes, if it resumes, and what the long-term effects of gender-affirming therapy are.
“This information is critical to address as part of a multidisciplinary fertility discussion with youth and their guardians so that an informed decision can be made regarding fertility preservation use,” wrote Emily P. Barnard, DO, of UPMC Magee-Womens Hospital in Pittsburgh and her associates.
The researchers retrospectively collected data on transgender patients who sought fertility preservation between 2015 and 2018.
The 11 white transgender women (sex assigned male at birth) who followed up on adolescent medicine or pediatric endocrinology referrals for fertility preservation received their consultations between ages 16 and 24, with 19 years having been the median age at which they occurred. Gender dysphoria onset happened at a median age of 12 for the patients, who were evaluated for it at a median age of 17.
All but one patient submitted at least one semen sample, and eight ultimately cryopreserved their semen.
The eight samples from gender-affirming therapy–naive patients had abnormal morphology, with the median morphology having been 6% versus the normal range of greater than 13.0%. Otherwise, the samples collected were normal, but the authors noted that established semen analysis parameters don’t exist for adolescents and young adults.
All eight patients who had their semen cryopreserved, began gonadotropin-releasing hormone (GnRH) agonist therapy after cryopreservation, and four of those patients concurrently began taking estradiol.
One patient had already been taking intramuscular leuprolide acetate every 6 months and discontinued it to attempt fertility preservation. Spermatogenesis returned after 5 months of azoospermia, albeit with abnormal morphology (9%).
Another patient had been taking spironolactone and estradiol for 26 months before ceasing therapy to attempt fertility preservation. She remained azoospermic 4 months after stopping therapy and then moved forward with an orchiectomy.
“For many transgender patients, the potential need to discontinue GnRH agonist or gender-affirming therapy to allow for resumption of spermatogenesis may be a significant barrier to pursuing fertility preservation because cessation of therapy may result in exacerbation of gender dysphoria and progression of undesired male secondary sex characteristics,” the researchers wrote. “For individuals for whom this risk is not acceptable or if azoospermia is noted on semen analysis, there are several alternate options, including electroejaculation, testicular sperm extraction, and testicular tissue cryopreservation,” they continued. Electroejaculation with a transrectal probe is an option particularly for those who cannot masturbate or feel uncomfortable doing so, the authors explained.
For those who have not previously received gender-affirming therapy, the fertility preservation “process can be completed quickly, with collections occurring every 2 to 3 days to preserve several samples before initiating GnRH agonist or gender-affirming therapy,” they concluded.
SOURCE: Barnard EP et al. Pediatrics. 2019 Aug 5. doi: 10.1542/peds.2018-3943.
The lack of long-term data on various gender-affirming medical interventions, particularly hormone therapies, for transgender adolescents and young adults has led professional medical organizations to recommend patients receive fertility counseling before beginning any such therapies.
Yet few data exist on fertility preservation either. The study by Barnard et al. is the first to examine semen cryopreservation outcomes in adolescents and young adults assigned male at birth and asserting a female gender identity.
“There is often urgency to start medical affirming interventions (MAI) among transgender and gender-diverse adolescents and young adults (TGD-AYA) due to gender dysphoria and related psychological sequelae,” wrote Jason Rafferty, MD, MPH, in an accompanying editorial. “However, starting MAI immediately and delaying fertility services may lead to increased overall morbidity for some patients.”
Although multiple professional organizations recommend fertility counseling before MAI initiation, many transgender patients are not following this advice. Dr. Rafferty noted one study found only 20% of TGD-AYA discussed fertility with their physicians before beginning MAI, and only 13% discussed possible effects of MAI on fertility – yet 60% wanted to learn more.
“Barnard et al. review data suggesting TGD-AYA have low interest in fertility services, but many TGD-AYA questioned whether this may later change,” Dr. Rafferty wrote. “After starting MAIs, TGD-AYA report being more emotionally capable of considering future parenting because of increasing comfort with their bodies and romantic relationships.”
Various barriers also exist for TGD-AYA interested in fertility services, such as cost, lack of insurance coverage, low availability of services, increased dysphoria from the procedures, stereotypes, stigma, and interest in starting MAI as soon as possible.
“Under a reproductive justice framework, autonomy around family planning is a right that should not be limited by structural or systemic barriers,” Dr. Rafferty wrote. “Overall, there is a clinical and ethical imperative to better understand and provide access to fertility services for TGD-AYA.”
Jason Rafferty, MD, MPH, is a pediatrician and child psychiatrist who practices at the gender and sexuality clinic in Riverside and at the Adolescent Healthcare Center at Hasbro Children’s Hospital in Providence, R.I. His comments are summarized from an accompanying editorial (Pediatrics 2019 Aug 5. doi: 10.1542/peds.2019-2000).
The lack of long-term data on various gender-affirming medical interventions, particularly hormone therapies, for transgender adolescents and young adults has led professional medical organizations to recommend patients receive fertility counseling before beginning any such therapies.
Yet few data exist on fertility preservation either. The study by Barnard et al. is the first to examine semen cryopreservation outcomes in adolescents and young adults assigned male at birth and asserting a female gender identity.
“There is often urgency to start medical affirming interventions (MAI) among transgender and gender-diverse adolescents and young adults (TGD-AYA) due to gender dysphoria and related psychological sequelae,” wrote Jason Rafferty, MD, MPH, in an accompanying editorial. “However, starting MAI immediately and delaying fertility services may lead to increased overall morbidity for some patients.”
Although multiple professional organizations recommend fertility counseling before MAI initiation, many transgender patients are not following this advice. Dr. Rafferty noted one study found only 20% of TGD-AYA discussed fertility with their physicians before beginning MAI, and only 13% discussed possible effects of MAI on fertility – yet 60% wanted to learn more.
“Barnard et al. review data suggesting TGD-AYA have low interest in fertility services, but many TGD-AYA questioned whether this may later change,” Dr. Rafferty wrote. “After starting MAIs, TGD-AYA report being more emotionally capable of considering future parenting because of increasing comfort with their bodies and romantic relationships.”
Various barriers also exist for TGD-AYA interested in fertility services, such as cost, lack of insurance coverage, low availability of services, increased dysphoria from the procedures, stereotypes, stigma, and interest in starting MAI as soon as possible.
“Under a reproductive justice framework, autonomy around family planning is a right that should not be limited by structural or systemic barriers,” Dr. Rafferty wrote. “Overall, there is a clinical and ethical imperative to better understand and provide access to fertility services for TGD-AYA.”
Jason Rafferty, MD, MPH, is a pediatrician and child psychiatrist who practices at the gender and sexuality clinic in Riverside and at the Adolescent Healthcare Center at Hasbro Children’s Hospital in Providence, R.I. His comments are summarized from an accompanying editorial (Pediatrics 2019 Aug 5. doi: 10.1542/peds.2019-2000).
The lack of long-term data on various gender-affirming medical interventions, particularly hormone therapies, for transgender adolescents and young adults has led professional medical organizations to recommend patients receive fertility counseling before beginning any such therapies.
Yet few data exist on fertility preservation either. The study by Barnard et al. is the first to examine semen cryopreservation outcomes in adolescents and young adults assigned male at birth and asserting a female gender identity.
“There is often urgency to start medical affirming interventions (MAI) among transgender and gender-diverse adolescents and young adults (TGD-AYA) due to gender dysphoria and related psychological sequelae,” wrote Jason Rafferty, MD, MPH, in an accompanying editorial. “However, starting MAI immediately and delaying fertility services may lead to increased overall morbidity for some patients.”
Although multiple professional organizations recommend fertility counseling before MAI initiation, many transgender patients are not following this advice. Dr. Rafferty noted one study found only 20% of TGD-AYA discussed fertility with their physicians before beginning MAI, and only 13% discussed possible effects of MAI on fertility – yet 60% wanted to learn more.
“Barnard et al. review data suggesting TGD-AYA have low interest in fertility services, but many TGD-AYA questioned whether this may later change,” Dr. Rafferty wrote. “After starting MAIs, TGD-AYA report being more emotionally capable of considering future parenting because of increasing comfort with their bodies and romantic relationships.”
Various barriers also exist for TGD-AYA interested in fertility services, such as cost, lack of insurance coverage, low availability of services, increased dysphoria from the procedures, stereotypes, stigma, and interest in starting MAI as soon as possible.
“Under a reproductive justice framework, autonomy around family planning is a right that should not be limited by structural or systemic barriers,” Dr. Rafferty wrote. “Overall, there is a clinical and ethical imperative to better understand and provide access to fertility services for TGD-AYA.”
Jason Rafferty, MD, MPH, is a pediatrician and child psychiatrist who practices at the gender and sexuality clinic in Riverside and at the Adolescent Healthcare Center at Hasbro Children’s Hospital in Providence, R.I. His comments are summarized from an accompanying editorial (Pediatrics 2019 Aug 5. doi: 10.1542/peds.2019-2000).
as transgender women, according to results of a small retrospective cohort study.
The lack of data on this topic, however, makes it difficult to determine how long an individual must be off gender-affirming therapy before spermatogenesis resumes, if it resumes, and what the long-term effects of gender-affirming therapy are.
“This information is critical to address as part of a multidisciplinary fertility discussion with youth and their guardians so that an informed decision can be made regarding fertility preservation use,” wrote Emily P. Barnard, DO, of UPMC Magee-Womens Hospital in Pittsburgh and her associates.
The researchers retrospectively collected data on transgender patients who sought fertility preservation between 2015 and 2018.
The 11 white transgender women (sex assigned male at birth) who followed up on adolescent medicine or pediatric endocrinology referrals for fertility preservation received their consultations between ages 16 and 24, with 19 years having been the median age at which they occurred. Gender dysphoria onset happened at a median age of 12 for the patients, who were evaluated for it at a median age of 17.
All but one patient submitted at least one semen sample, and eight ultimately cryopreserved their semen.
The eight samples from gender-affirming therapy–naive patients had abnormal morphology, with the median morphology having been 6% versus the normal range of greater than 13.0%. Otherwise, the samples collected were normal, but the authors noted that established semen analysis parameters don’t exist for adolescents and young adults.
All eight patients who had their semen cryopreserved, began gonadotropin-releasing hormone (GnRH) agonist therapy after cryopreservation, and four of those patients concurrently began taking estradiol.
One patient had already been taking intramuscular leuprolide acetate every 6 months and discontinued it to attempt fertility preservation. Spermatogenesis returned after 5 months of azoospermia, albeit with abnormal morphology (9%).
Another patient had been taking spironolactone and estradiol for 26 months before ceasing therapy to attempt fertility preservation. She remained azoospermic 4 months after stopping therapy and then moved forward with an orchiectomy.
“For many transgender patients, the potential need to discontinue GnRH agonist or gender-affirming therapy to allow for resumption of spermatogenesis may be a significant barrier to pursuing fertility preservation because cessation of therapy may result in exacerbation of gender dysphoria and progression of undesired male secondary sex characteristics,” the researchers wrote. “For individuals for whom this risk is not acceptable or if azoospermia is noted on semen analysis, there are several alternate options, including electroejaculation, testicular sperm extraction, and testicular tissue cryopreservation,” they continued. Electroejaculation with a transrectal probe is an option particularly for those who cannot masturbate or feel uncomfortable doing so, the authors explained.
For those who have not previously received gender-affirming therapy, the fertility preservation “process can be completed quickly, with collections occurring every 2 to 3 days to preserve several samples before initiating GnRH agonist or gender-affirming therapy,” they concluded.
SOURCE: Barnard EP et al. Pediatrics. 2019 Aug 5. doi: 10.1542/peds.2018-3943.
as transgender women, according to results of a small retrospective cohort study.
The lack of data on this topic, however, makes it difficult to determine how long an individual must be off gender-affirming therapy before spermatogenesis resumes, if it resumes, and what the long-term effects of gender-affirming therapy are.
“This information is critical to address as part of a multidisciplinary fertility discussion with youth and their guardians so that an informed decision can be made regarding fertility preservation use,” wrote Emily P. Barnard, DO, of UPMC Magee-Womens Hospital in Pittsburgh and her associates.
The researchers retrospectively collected data on transgender patients who sought fertility preservation between 2015 and 2018.
The 11 white transgender women (sex assigned male at birth) who followed up on adolescent medicine or pediatric endocrinology referrals for fertility preservation received their consultations between ages 16 and 24, with 19 years having been the median age at which they occurred. Gender dysphoria onset happened at a median age of 12 for the patients, who were evaluated for it at a median age of 17.
All but one patient submitted at least one semen sample, and eight ultimately cryopreserved their semen.
The eight samples from gender-affirming therapy–naive patients had abnormal morphology, with the median morphology having been 6% versus the normal range of greater than 13.0%. Otherwise, the samples collected were normal, but the authors noted that established semen analysis parameters don’t exist for adolescents and young adults.
All eight patients who had their semen cryopreserved, began gonadotropin-releasing hormone (GnRH) agonist therapy after cryopreservation, and four of those patients concurrently began taking estradiol.
One patient had already been taking intramuscular leuprolide acetate every 6 months and discontinued it to attempt fertility preservation. Spermatogenesis returned after 5 months of azoospermia, albeit with abnormal morphology (9%).
Another patient had been taking spironolactone and estradiol for 26 months before ceasing therapy to attempt fertility preservation. She remained azoospermic 4 months after stopping therapy and then moved forward with an orchiectomy.
“For many transgender patients, the potential need to discontinue GnRH agonist or gender-affirming therapy to allow for resumption of spermatogenesis may be a significant barrier to pursuing fertility preservation because cessation of therapy may result in exacerbation of gender dysphoria and progression of undesired male secondary sex characteristics,” the researchers wrote. “For individuals for whom this risk is not acceptable or if azoospermia is noted on semen analysis, there are several alternate options, including electroejaculation, testicular sperm extraction, and testicular tissue cryopreservation,” they continued. Electroejaculation with a transrectal probe is an option particularly for those who cannot masturbate or feel uncomfortable doing so, the authors explained.
For those who have not previously received gender-affirming therapy, the fertility preservation “process can be completed quickly, with collections occurring every 2 to 3 days to preserve several samples before initiating GnRH agonist or gender-affirming therapy,” they concluded.
SOURCE: Barnard EP et al. Pediatrics. 2019 Aug 5. doi: 10.1542/peds.2018-3943.
FROM PEDIATRICS
Osteonecrosis of the femoral head with subchondral collapse
A 45-year-old woman with a history of multiple organ transplants presented with a 1-month history of anterior left hip pain with insidious onset. Although she was able to perform activities of daily living, she reported increasing difficulty with weight-bearing activities.
RISK FACTORS
Osteonecrosis of the hip is caused by prolonged interruption of blood flow to the femoral head.2 While idiopathic osteonecrosis is not uncommon, the condition is often associated with alcohol abuse or, as in our patient, long-term corticosteroid use after organ transplant.3 Corticosteroid use is also the most frequently reported risk factor for multifocal osteonecrosis.
Less common risk factors include systemic lupus erythematosus, antiphospholipid antibodies, coagulopathies, sickle cell disease, Gaucher disease, trauma, and external-beam therapy.
Young age is also associated with osteonecrosis, as nearly 75% of patients are between age 30 and 60.4
APPROACH TO DIAGNOSIS
Our patient had a typical clinical presentation of this disease: she was relatively young, was on long-term corticosteroids, and had acute anterior groin pain followed by progressive functional impairment.
The diagnostic evaluation consists of a detailed history, with attention to specific risk factors, and a thorough clinical examination followed by imaging, usually with plain radiography. However, plain radiographs are often unremarkable when the condition is in the early stages. In such cases, magnetic resonance imaging is recommended if clinical suspicion for osteonecrosis is high. It is far more sensitive (> 99%) and specific (> 99%) than plain radiography, and it detects early changes in the femoral head such as focal lesions and bone marrow edema.5
TREATMENT OPTIONS
Treatment of osteonecrosis is surgical and depends on the stage of disease.6
Joint preservation may be an option for small to medium-sized lesions before subchondral collapse has occurred; options include core decompression, bone grafting, and femoral osteotomy to preserve the native femoral head. These procedures have a higher success rate in young patients.
Subchondral collapse usually warrants hip replacement.
OUR PATIENT’S TREATMENT
- Pappas JN. The musculoskeletal crescent sign. Radiology 2000; 217(1):213–214. doi:10.1148/radiology.217.1.r00oc22213
- Shah KN, Racine J, Jones LC, Aaron RK. Pathophysiology and risk factors for osteonecrosis. Curr Rev Musculoskelet Med 2015; 8(3):201–209. doi:10.1007/s12178-015-9277-8
- Moya-Angeler J, Gianakos AL, Villa JC, Ni A, Lane JM. Current concepts on osteonecrosis of the femoral head. World J Orthop 2015; 6(8):590–601. doi:10.5312/wjo.v6.i8.590
- Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002; 32(2):94–124. pmid:12430099
- Pierce TP, Jauregui JJ, Cherian JJ, Elmallah RK, Mont MA. Imaging evaluation of patients with osteonecrosis of the femoral head. Curr Rev Musculoskelet Med 2015; 8(3):221–227. doi:10.1007/s12178-015-9279-6
- Chughtai M, Piuzzi NS, Khlopas A, Jones LC, Goodman SB, Mont MA. An evidence-based guide to the treatment of osteonecrosis of the femoral head. Bone Joint J 2017; 99-B(10):1267–1279. doi:10.1302/0301-620X.99B10.BJJ-2017-0233.R2
A 45-year-old woman with a history of multiple organ transplants presented with a 1-month history of anterior left hip pain with insidious onset. Although she was able to perform activities of daily living, she reported increasing difficulty with weight-bearing activities.
RISK FACTORS
Osteonecrosis of the hip is caused by prolonged interruption of blood flow to the femoral head.2 While idiopathic osteonecrosis is not uncommon, the condition is often associated with alcohol abuse or, as in our patient, long-term corticosteroid use after organ transplant.3 Corticosteroid use is also the most frequently reported risk factor for multifocal osteonecrosis.
Less common risk factors include systemic lupus erythematosus, antiphospholipid antibodies, coagulopathies, sickle cell disease, Gaucher disease, trauma, and external-beam therapy.
Young age is also associated with osteonecrosis, as nearly 75% of patients are between age 30 and 60.4
APPROACH TO DIAGNOSIS
Our patient had a typical clinical presentation of this disease: she was relatively young, was on long-term corticosteroids, and had acute anterior groin pain followed by progressive functional impairment.
The diagnostic evaluation consists of a detailed history, with attention to specific risk factors, and a thorough clinical examination followed by imaging, usually with plain radiography. However, plain radiographs are often unremarkable when the condition is in the early stages. In such cases, magnetic resonance imaging is recommended if clinical suspicion for osteonecrosis is high. It is far more sensitive (> 99%) and specific (> 99%) than plain radiography, and it detects early changes in the femoral head such as focal lesions and bone marrow edema.5
TREATMENT OPTIONS
Treatment of osteonecrosis is surgical and depends on the stage of disease.6
Joint preservation may be an option for small to medium-sized lesions before subchondral collapse has occurred; options include core decompression, bone grafting, and femoral osteotomy to preserve the native femoral head. These procedures have a higher success rate in young patients.
Subchondral collapse usually warrants hip replacement.
OUR PATIENT’S TREATMENT
A 45-year-old woman with a history of multiple organ transplants presented with a 1-month history of anterior left hip pain with insidious onset. Although she was able to perform activities of daily living, she reported increasing difficulty with weight-bearing activities.
RISK FACTORS
Osteonecrosis of the hip is caused by prolonged interruption of blood flow to the femoral head.2 While idiopathic osteonecrosis is not uncommon, the condition is often associated with alcohol abuse or, as in our patient, long-term corticosteroid use after organ transplant.3 Corticosteroid use is also the most frequently reported risk factor for multifocal osteonecrosis.
Less common risk factors include systemic lupus erythematosus, antiphospholipid antibodies, coagulopathies, sickle cell disease, Gaucher disease, trauma, and external-beam therapy.
Young age is also associated with osteonecrosis, as nearly 75% of patients are between age 30 and 60.4
APPROACH TO DIAGNOSIS
Our patient had a typical clinical presentation of this disease: she was relatively young, was on long-term corticosteroids, and had acute anterior groin pain followed by progressive functional impairment.
The diagnostic evaluation consists of a detailed history, with attention to specific risk factors, and a thorough clinical examination followed by imaging, usually with plain radiography. However, plain radiographs are often unremarkable when the condition is in the early stages. In such cases, magnetic resonance imaging is recommended if clinical suspicion for osteonecrosis is high. It is far more sensitive (> 99%) and specific (> 99%) than plain radiography, and it detects early changes in the femoral head such as focal lesions and bone marrow edema.5
TREATMENT OPTIONS
Treatment of osteonecrosis is surgical and depends on the stage of disease.6
Joint preservation may be an option for small to medium-sized lesions before subchondral collapse has occurred; options include core decompression, bone grafting, and femoral osteotomy to preserve the native femoral head. These procedures have a higher success rate in young patients.
Subchondral collapse usually warrants hip replacement.
OUR PATIENT’S TREATMENT
- Pappas JN. The musculoskeletal crescent sign. Radiology 2000; 217(1):213–214. doi:10.1148/radiology.217.1.r00oc22213
- Shah KN, Racine J, Jones LC, Aaron RK. Pathophysiology and risk factors for osteonecrosis. Curr Rev Musculoskelet Med 2015; 8(3):201–209. doi:10.1007/s12178-015-9277-8
- Moya-Angeler J, Gianakos AL, Villa JC, Ni A, Lane JM. Current concepts on osteonecrosis of the femoral head. World J Orthop 2015; 6(8):590–601. doi:10.5312/wjo.v6.i8.590
- Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002; 32(2):94–124. pmid:12430099
- Pierce TP, Jauregui JJ, Cherian JJ, Elmallah RK, Mont MA. Imaging evaluation of patients with osteonecrosis of the femoral head. Curr Rev Musculoskelet Med 2015; 8(3):221–227. doi:10.1007/s12178-015-9279-6
- Chughtai M, Piuzzi NS, Khlopas A, Jones LC, Goodman SB, Mont MA. An evidence-based guide to the treatment of osteonecrosis of the femoral head. Bone Joint J 2017; 99-B(10):1267–1279. doi:10.1302/0301-620X.99B10.BJJ-2017-0233.R2
- Pappas JN. The musculoskeletal crescent sign. Radiology 2000; 217(1):213–214. doi:10.1148/radiology.217.1.r00oc22213
- Shah KN, Racine J, Jones LC, Aaron RK. Pathophysiology and risk factors for osteonecrosis. Curr Rev Musculoskelet Med 2015; 8(3):201–209. doi:10.1007/s12178-015-9277-8
- Moya-Angeler J, Gianakos AL, Villa JC, Ni A, Lane JM. Current concepts on osteonecrosis of the femoral head. World J Orthop 2015; 6(8):590–601. doi:10.5312/wjo.v6.i8.590
- Assouline-Dayan Y, Chang C, Greenspan A, Shoenfeld Y, Gershwin ME. Pathogenesis and natural history of osteonecrosis. Semin Arthritis Rheum 2002; 32(2):94–124. pmid:12430099
- Pierce TP, Jauregui JJ, Cherian JJ, Elmallah RK, Mont MA. Imaging evaluation of patients with osteonecrosis of the femoral head. Curr Rev Musculoskelet Med 2015; 8(3):221–227. doi:10.1007/s12178-015-9279-6
- Chughtai M, Piuzzi NS, Khlopas A, Jones LC, Goodman SB, Mont MA. An evidence-based guide to the treatment of osteonecrosis of the femoral head. Bone Joint J 2017; 99-B(10):1267–1279. doi:10.1302/0301-620X.99B10.BJJ-2017-0233.R2
Gastroparesis
To the Editor: We read with great pleasure the article by Sharayah et al about acute gastroparesis in a patient with diabetic ketoacidosis.1 However, in the case description, the authors reached a diagnosis of gastroparesis secondary to diabetic ketoacidosis without aptly ruling out some of its most common causes such as hypokalemia and other electrolyte imbalances seen in diabetic patients (in the setting of recurrent vomiting).
The authors also did not include the patient’s duration of diabetes or hemoglobin A1c level, both of which are linked with gastroparesis in diabetic patients.2 Pertinent biochemical information that can help readers formulate a rational approach and journey to making a diagnosis appears elusive in their article.
- Sharayah AM, Hajjaj N, Osman R, Livornese D. Gastroparesis in a patient with diabetic ketoacidosis. Cleve Clin J Med 2019; 86(4):238–239. doi:10.3949/ccjm.86a.18116
- Bharucha AE, Kudva Y, Basu A, et al. Relationship between glycemic control and gastric emptying in poorly controlled type 2 diabetes. Clin Gastroenterol Hepatol 2015; 13(3):466–476.e461. doi:10.1016/j.cgh.2014.06.034
To the Editor: We read with great pleasure the article by Sharayah et al about acute gastroparesis in a patient with diabetic ketoacidosis.1 However, in the case description, the authors reached a diagnosis of gastroparesis secondary to diabetic ketoacidosis without aptly ruling out some of its most common causes such as hypokalemia and other electrolyte imbalances seen in diabetic patients (in the setting of recurrent vomiting).
The authors also did not include the patient’s duration of diabetes or hemoglobin A1c level, both of which are linked with gastroparesis in diabetic patients.2 Pertinent biochemical information that can help readers formulate a rational approach and journey to making a diagnosis appears elusive in their article.
To the Editor: We read with great pleasure the article by Sharayah et al about acute gastroparesis in a patient with diabetic ketoacidosis.1 However, in the case description, the authors reached a diagnosis of gastroparesis secondary to diabetic ketoacidosis without aptly ruling out some of its most common causes such as hypokalemia and other electrolyte imbalances seen in diabetic patients (in the setting of recurrent vomiting).
The authors also did not include the patient’s duration of diabetes or hemoglobin A1c level, both of which are linked with gastroparesis in diabetic patients.2 Pertinent biochemical information that can help readers formulate a rational approach and journey to making a diagnosis appears elusive in their article.
- Sharayah AM, Hajjaj N, Osman R, Livornese D. Gastroparesis in a patient with diabetic ketoacidosis. Cleve Clin J Med 2019; 86(4):238–239. doi:10.3949/ccjm.86a.18116
- Bharucha AE, Kudva Y, Basu A, et al. Relationship between glycemic control and gastric emptying in poorly controlled type 2 diabetes. Clin Gastroenterol Hepatol 2015; 13(3):466–476.e461. doi:10.1016/j.cgh.2014.06.034
- Sharayah AM, Hajjaj N, Osman R, Livornese D. Gastroparesis in a patient with diabetic ketoacidosis. Cleve Clin J Med 2019; 86(4):238–239. doi:10.3949/ccjm.86a.18116
- Bharucha AE, Kudva Y, Basu A, et al. Relationship between glycemic control and gastric emptying in poorly controlled type 2 diabetes. Clin Gastroenterol Hepatol 2015; 13(3):466–476.e461. doi:10.1016/j.cgh.2014.06.034
