Critical illness is associated with increased bone turnover, loss of bone density, and increased risk of fragility fractures. The impact of bone antiresorptive agents in this population is not ...established. This trial examined the efficacy, feasibility, and safety of antiresorptive agents administered to critically ill women aged fifty years or greater. Women aged 50 years or greater admitted to an intensive care unit for at least 24 h were randomised to receive an antiresorptive agent (zoledronic acid or denosumab) or placebo, during critical illness and six months later (denosumab only). Bone turnover markers and bone mineral density (BMD) were monitored for 1 year. We studied 18 patients over 35 months before stopping the study due to the COVID-19 pandemic. Antiresorptive medications decreased the bone turnover marker type 1 cross-linked c-telopeptide (CTX) from day 0 to 28 by 43% (± 40%), compared to an increase of 26% (± 55%) observed with placebo (absolute difference - 69%, 95% CI - 127% to - 11%), p = 0.03). Mixed linear modelling revealed differences in the month after trial drug administration between the groups in serum CTX, alkaline phosphatase, parathyroid hormone, and phosphate. Change in BMD between antiresorptive and placebo groups was not statistically analysed due to small numbers. No serious adverse events were recorded. In critically ill women aged 50-years and over, antiresorptive agents suppressed bone resorption markers without serious adverse events. However, recruitment was slow. Further phase 2 trials examining the efficacy of these agents are warranted and should address barriers to enrolment.Trial registration: ACTRN12617000545369, registered 18th April 2017.
Intensive care unit (ICU) survivors have reduced physical function likely due to skeletal muscle wasting and weakness acquired during critical illness. However, the contribution of pre-morbid muscle ...mass has not been elucidated. We aimed to examine the association between pre-ICU muscle mass and ICU admission risk. Secondary outcomes include the relationship between muscle mass and ICU outcomes.
ICU admissions between June 1, 1998, and February 1, 2019, were identified among participants of Geelong Osteoporosis Study (GOS), a population-based cohort study. Cox proportional hazard regression models estimated hazard ratios (HR) for ICU admission across T-score strata and continuous values of DXA-derived lean mass measures of skeletal mass index (SMI, lean mass/body mass %) and appendicular lean mass corrected for height (ALM/h
, kg/m
). Multivariable regression was used to determine the relationship between lean mass and ICU outcomes.
One hundred and eighty-six of 3126 participants enrolled in GOS were admitted to the ICU during the follow-up period. In adjusted models, lean mass was not predictive of ICU admission (SMI: HR 0.99 95%CI 0.97-1.01, p = 0.32; ALM/h
: HR 1.11 95%CI 0.94-1.31, p = 0.23), while greater appendicular lean mass was related to reduced 28-day mortality (ALM/h
adjOR: 0.25, 95%CI 0.10-0.63, p = 0.003, SMI adjOR: 0.91, 95%CI 0.82-1.02, p = 0.09).
Lean mass was not associated with ICU admission in this population-based cohort study; however, greater appendicular lean mass was associated with reduced mortality. This suggests pre-ICU muscle status may not predict development of critical illness but is associated with better survival after critical illness occurs.
Whole-body dual X-ray absorptiometry (DXA) accurately measures lean mass but is not routinely used in clinical practice. Hip and spine DXA are used in the diagnosis of osteoporosis, and with the ...common co-occurrence of sarcopenia with osteoporosis, regional DXA scans provide an opportunity for assessment of lean mass. The aim of this study is to develop predictive equations for the estimation of whole-body lean mass (WBLM), appendicular lean mass (ALM) and whole-body fat mass (WBFM) from regional DXA scans. A total of 2427 participants (ages 20–96 year; 57.7% men) from the Geelong Osteoporosis Study who underwent both regional and whole-body DXA were included in the analysis. Using forward stepwise multivariable linear regression, percentage fat (spine%fat, hip%fat) values from lumbar spine and femoral neck DXA were used in combination with clinical data to develop and validate equations for the estimation of WBLM, WBFM and ALM. Mean age was 53.5 year (± 19.2), weight 78.2 kg (± 15.4), height 169.6 cm (± 9.4), WBLM 50.4 kg (± 11.1), ALM 22.8 kg (± 5.4) and WBFM 24.3 kg (± 10.4). Spine%fat (
r
= 0.21) and hip%fat (
r
= − 0.34) were correlated with whole-body lean mass (
p
< 0.001). Final predictive equations included age, sex, weight, height, spine%fat, and hip%fat and possessed high predictive value (Adj
R
2
0.91–0.94, RMSE 1.60–2.84 kg).
K
-fold cross-validation methods produced median root mean square error (RMSE) ranging from 1.59 to 2.81 kg for the three models. Regional DXA scans of the spine and hip can be used to estimate whole-body and appendicular lean mass, to assist in the identification of low muscle mass.
Improved survival after critical illness has led to recognition of impaired recovery following critical illness as a major public health problem. A consistent association between critical illness and ...accelerated bone loss has been described, including changes in bone turnover markers, bone mineral density, and fragility fracture rate. An association between accelerated bone turnover and increased mortality after critical illness is probable. Assessment of the effect of antifracture agents on fracture rate and mortality in the high-risk population of postmenopausal women with prolonged ventilation is warranted.
Critical illness may be associated with increased bone turnover and loss of bone mineral density (BMD). Prospective evidence describing long-term changes in BMD after critical illness is needed to ...further define this relationship.
To measure the change in BMD and bone turnover markers (BTMs) in subjects 1 year after critical illness compared with population-based control subjects.
We studied adult patients admitted to a tertiary intensive care unit (ICU) who required mechanical ventilation for at least 24 hours. We measured clinical characteristics, BTMs, and BMD during admission and 1 year after ICU discharge. We compared change in BMD to age- and sex-matched control subjects from the Geelong Osteoporosis Study.
Sixty-six patients completed BMD testing. BMD decreased significantly in the year after critical illness at both femoral neck and anterior-posterior spine sites. The annual decrease was significantly greater in the ICU cohort compared with matched control subjects (anterior-posterior spine, -1.59%; 95% confidence interval, -2.18 to -1.01; P < 0.001; femoral neck, -1.20%; 95% confidence interval, -1.69 to -0.70; P < 0.001). There was a significant increase in 10-year fracture risk for major fractures (4.85 ± 5.25 vs. 5.50 ± 5.52; P < 0.001) and hip fractures (1.57 ± 2.40 vs. 1.79 ± 2.69; P = 0.001). The pattern of bone resorption markers was consistent with accelerated bone turnover.
Critically ill individuals experience a significantly greater decrease in BMD in the year after admission compared with population-based control subjects. Their bone turnover biomarker pattern is consistent with an increased rate of bone loss.
Critical illness is associated with increased risk of fragility fracture and loss of bone mineral density (BMD), although the impact of medication exposures (bone anti-fracture therapy or ...glucocorticoids) and time remain unexplored. The objective of this study was to describe the association of time after ICU admission, and post-ICU administration of bone anti-fracture therapy or glucocorticoids after critical illness, with change in BMD.
In this prospective observational study, conducted in a tertiary hospital ICU, we studied adult patients requiring mechanical ventilation for at least 24 hours and measured BMD annually for 2 years after ICU discharge. We performed mixed linear modelling to describe the association of time, and post-ICU administration of anti-fracture therapy or glucocorticoids, with annualised change in BMD.
Ninety-two participants with a mean age of 63 (±15) years had at least one BMD assessment after ICU discharge. In women, a greater loss of spine BMD occurred in the first year after critical illness (year 1: -1.1 ± 2.0% vs year 2: 3.0 ± 1.7%, p = 0.02), and anti-fracture therapy use was associated with reduced loss of BMD (femur 3.1 ± 2.4% vs -2.8 ± 1.7%, p = 0.04, spine 5.1 ± 2.5% vs -3.2 ± 1.8%, p = 0.01). In men anti-fracture and glucocorticoid use were not associated with change in BMD, and a greater decrease in BMD occurred in the second year after critical illness (year 1: -0.9 ± 2.1% vs year 2: -2.5 ± 2.1%, p = 0.03).
In women a greater loss of spine BMD was observed in the first year after critical illness, and anti-fracture therapy use was associated with an increase in BMD. In men BMD loss increased in the second year after critical illness. Anti-fracture therapy may be an effective intervention to prevent bone loss in women after critical illness.
How does human brain structure mature during adolescence? We used MRI to measure cortical thickness and intracortical myelination in 297 population volunteers aged 14–24 y old. We found and ...replicated that association cortical areas were thicker and less myelinated than primary cortical areas at 14 y. However, association cortex had faster rates of shrinkage and myelination over the course of adolescence. Age-related increases in cortical myelination were maximized approximately at the internal layer of projection neurons. Adolescent cortical myelination and shrinkage were coupled and specifically associated with a dorsoventrally patterned gene expression profile enriched for synaptic, oligodendroglial- and schizophrenia-related genes. Topologically efficient and biologically expensive hubs of the brain anatomical network had greater rates of shrinkage/myelination and were associated with overexpression of the same transcriptional profile as cortical consolidation. We conclude that normative human brain maturation involves a genetically patterned process of consolidating anatomical network hubs. We argue that developmental variation of this consolidation process may be relevant both to normal cognitive and behavioral changes and the high incidence of schizophrenia during human brain adolescence.
When building causal knowledge in behavioural genetics, the natural randomisation of genotypes at conception (approximately analogous to the artificial randomisation occurring in randomised ...controlled trials) facilitates the discovery of genetic causes. More importantly, the randomisation of genetic material within families also enables a better identification of (environmental) risk factors and aetiological pathways to diseases and behaviours.
Summary
The contribution of premorbid bone health to accelerated bone loss following critical illness is unknown. This study compared bone density in women before critical illness to women who did ...not become critically ill. Overall bone density was similar, although femoral neck bone mass increased immediately prior to critical illness.
Purpose
The relative contribution of acute and chronic factors to accelerated loss of bone mineral density (BMD) following critical illness is unknown. This study compared the BMD trajectory of women before critical illness to the BMD trajectory of women who did not become critically ill.
Methods
This prospective, nested, age- and medication-matched, case-control study compared trajectory of BMD in women in the Geelong Osteoporosis study (GOS) requiring admission to an Australian Intensive Care Unit (ICU) between June 1998 and March 2016, to women not admitted to ICU. The main outcome was age and medication use adjusted change in BMD.
Results
A total of 52 women, with a mean age of 77 ± 9 years were admitted to ICU, predominantly post-surgery (75%), during the study period. A greater age-adjusted annual rate of decline was observed for pre-ICU women compared to no-ICU women for AP spine BMD (−0.010 ± 0.002 g/cm
2
vs −0.005 ± 0.002 g/cm
2
,
p
= 0.01) over the 15-year study period. In participants with multiple BMDs 2 years before critical illness, a significantly greater increase in femoral neck BMD compared to age- and medication-matched controls was observed (difference in BMD, ICU vs no-ICU = 0.037 ± 0.013 g/cm
2
,
p
= 0.006).
Conclusion
In a cohort of women with predominantly surgical ICU admission, bone health prior to critical illness was comparable to age- and medication-matched controls, with a relative increase in femoral neck bone mass immediately prior to critical illness. These findings suggest critical illness-related bone loss cannot be entirely explained as a continuation of pre-morbid bone trajectory.
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