| 1. |
- Marouli, Eirini, et al.
(author)
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Rare and low-frequency coding variants alter human adult height
- 2017
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 542:7640, s. 186-190
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Journal article (peer-reviewed)abstract
- Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
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| 2. |
- Jamal, Sophie A., et al.
(author)
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Effects of Denosumab on Fracture and Bone Mineral Density by Level of Kidney Function
- 2011
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In: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 26:8, s. 1829-1835
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Journal article (peer-reviewed)abstract
- The incidences of osteoporosis and chronic kidney disease (CKD) both increase with increasing age, yet there is a paucity of data on treatments for osteoporosis in the setting of impaired kidney function. We examined the efficacy and safety of denosumab (DMAb) among subjects participating in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6Months (FREEDOM) Study. We estimated creatinine clearance (eGFR) using Cockcroft-Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. We examined incident fracture rates; changes in bone mineral density (BMD), serum calcium, and creatinine; and the incidence of adverse events after 36 months of follow-up in subjects receiving DMAb or placebo, stratified by level of kidney function. We used a subgroup interaction term to determine if there were differences in treatment effect by eGFR. Most (93%) women were white, and the mean age was 72.3 +/- 5.2 years; 73 women had an eGFR of 15 to 29mL/min; 2817, between 30 to 59mL/min; 4069, between 60 to 89mL/min, and 842 had an eGFR of 90mL/min or greater. None had stage 5 CKD. Fracture risk reduction and changes in BMD at all sites were in favor of DMAb. The test for treatment by subgroup interaction was not statistically significant, indicating that treatment efficacy did not differ by kidney function. Changes in creatinine and calcium and the incidence of adverse events were similar between groups and did not differ by level of kidney function. It is concluded that DMAb is effective at reducing fracture risk and is not associated with an increase in adverse events among patients with impaired kidney function.
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| 3. |
- Scott, David, et al.
(author)
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Adiposity Without Obesity : Associations with Osteoporosis, Sarcopenia, and Falls in the Healthy Ageing Initiative Cohort Study
- 2020
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In: Obesity. - : John Wiley & Sons. - 1930-7381 .- 1930-739X. ; 28:11, s. 2232-2241
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Journal article (peer-reviewed)abstract
- Objective: Obesity is commonly defined by BMI rather than adiposity, which may have differential effects on musculoskeletal health. Musculoskeletal outcomes were compared in older adults with normal adiposity and normal BMI (NA‐NBMI), those with high adiposity but normal BMI (HA‐NBMI), and those with high adiposity and high BMI (HA‐HBMI).Methods: In 3,411 70‐year‐olds, obesity was defined as BMI ≥ 30 kg/m2 and adiposity as body fat percentage ≥ 25% (men) or ≥ 35% (women) from dual‐energy x‐ray absorptiometry. Bone parameters were measured by dual‐energy x‐ray absorptiometry and peripheral quantitative computed tomography. Sarcopenia was defined as low handgrip strength with or without low appendicular lean mass. Falls were self‐reported 6 and 12 months later.Results: Prevalence of NA‐NBMI, HA‐NBMI, and HA‐HBMI was 14.2%, 68.1%, and 17.7%, respectively. Compared with HA‐HBMI, HA‐NBMI had increased likelihood for sarcopenia (adjusted odds ratio: 3.99; 95% CI: 1.41‐11.32) and osteoporosis (2.91; 95% CI: 2.35‐3.61) but similar likelihood of falls (P > 0.05). HA‐NBMI had lower values for bone geometry parameters, as well as grip strength, than both NA‐NBMI and HA‐HBMI (all P < 0.05).Conclusions: High adiposity without high BMI is more common than BMI‐defined obesity in older Swedish adults but does not provide similar protection from osteoporosis and sarcopenia.
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| 4. |
- Scott, David, et al.
(author)
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Associations of accelerometer-determined physical activity and sedentary behavior with sarcopenia and incident falls over 12 months in community-dwelling Swedish older adults
- 2021
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In: Journal of Sport and Health Science. - Shanghai : Shanghai University of Sports. - 2095-2546 .- 2213-2961. ; 10:5, s. 577-584
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Journal article (peer-reviewed)abstract
- Purpose: This study was aimed to determine associations of accelerometer-determined time and bouts of sedentary behavior, light physical activity (LPA), and moderate-to-vigorous PA (MVPA) with sarcopenia and incident falls over 12 months.Methods: A total of 3334 Swedish 70-year-olds were assessed for sarcopenia, as defined by the revised definition of the European Working Group on Sarcopenia in Older People. Assessments were based on low scores for appendicular lean mass (dual-energy X-ray absorptiometry), hand grip strength, and the Timed Up and Go test. For 7 days after baseline, total time and total number of bouts (>10 min of continuous activity at a given intensity) of activity performed at sedentary, LPA, and MVPA intensities were assessed by accelerometer. Incident falls were self-reported 6 months and 12 months after baseline.Results: Only 1.8% of participants had probable or confirmed sarcopenia. After multivariable adjustment for other levels of activity, only greater MVPA time was associated with a decreased likelihood of having low appendicular lean mass, low hand grip strength, and slow Timed Up and Go time as defined by the European Working Group on Sarcopenia in Older People criteria (all p < 0.05), and only MVPA time was associated with lower likelihood of probable or confirmed sarcopenia (odds ratio = 0.80, 95% confidence interval: 0.71-0.91 h/week). Similar associations were identified for total number of bouts, with no evidence of threshold effects for longer duration of bouts of MVPA. A total of 14% of participants reported >1 fall, but neither total time nor bouts of activity was associated with incident falls (all p > 0.05).Conclusion: Higher amounts of accelerometer-determined MVPA are consistently associated with a decreased likelihood of sarcopenia and its components, regardless of the length of bouts or amounts of sedentary behavior.
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| 5. |
- Scott, David, et al.
(author)
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Associations of Sarcopenia and Its Components with Bone Structure and Incident Falls in Swedish Older Adults
- 2019
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In: Calcified Tissue International. - : Springer. - 0171-967X .- 1432-0827. ; 105:1, s. 26-36
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Journal article (peer-reviewed)abstract
- The aim of this study was to compare bone structure parameters and likelihood of falls across European Working Group on Sarcopenia in Older People (EWGSOP2) sarcopenia categories. 3334 Swedish 70-year olds had appendicular lean mass (normalized to height; ALMHt), lumbar spine and total hip areal BMD (aBMD) estimated by dual-energy X-ray absorptiometry. Volumetric BMD (vBMD) and structure at the distal and proximal tibia and radius were estimated by peripheral quantitative computed tomography. Hand grip strength and timed up-and-go were assessed, and sarcopenia was defined according to EWGSOP2 criteria. Incident falls were self-reported 6 and 12 months after baseline. Only 0.8% and 1.0% of participants had probable and confirmed sarcopenia, respectively. Almost one-third of participants with confirmed sarcopenia reported incident falls, compared with 20% for probable sarcopenia and 14% without sarcopenia (P = 0.025). Participants with confirmed sarcopenia had poorer bone parameters (all P < 0.05) except endosteal circumference at the proximal radius and tibia, while those with probable sarcopenia had lower cortical area at the proximal radius (B = - 5.9; 95% CI - 11.7, - 0.1 mm2) and periosteal and endosteal circumferences at the proximal tibia (- 3.3; - 6.4, - 0.3 and - 3.8; - 7.5, - 0.1 mm2, respectively), compared with those without sarcopenia. Compared with probable sarcopenia, confirmed sarcopenic participants had significantly lower lumbar spine and total hip aBMD, distal radius and tibia total vBMD, and proximal radius and tibia cortical vBMD, area and thickness (all P < 0.05). Swedish 70-year olds with confirmed sarcopenia demonstrate poorer BMD and bone architecture than those with probable and no sarcopenia, and have increased likelihood of incident falls.
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| 6. |
- Scott, David, et al.
(author)
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Mid-calf skeletal muscle density and its associations with physical activity, bone health and incident 12-month falls in older adults : The Healthy Ageing Initiative
- 2019
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In: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 120, s. 446-451
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Journal article (peer-reviewed)abstract
- BACKGROUND: Lower skeletal muscle density, indicating greater infiltration of adipose tissue into muscles, is associated with higher fracture risk in older adults. We aimed to determine whether mid-calf muscle density is associated with falls risk and bone health in community-dwelling older adults.METHODS: 2214 community-dwelling men and women who participated in the Healthy Ageing Initiative (Sweden) study at age 70 were included in this analysis. Mid-calf muscle density (mg/cm3) at the proximal tibia, and volumetric bone mineral density (vBMD) and architecture at the distal and proximal tibia and radius, were assessed by peripheral quantitative computed tomography. Whole-body lean and fat mass, lumbar spine and total hip areal bone mineral density (aBMD) were assessed by dual-energy X-ray absorptiometry. Participants completed seven-day accelerometer measurements of physical activity intensity, and self-reported falls data were collected 6 and 12 months later.RESULTS: 302 (13.5%) participants reported a fall at the 6- or 12-month interview, and 29 (1.3%) reported a fall at both interviews. After adjustment for confounders, each standard deviation decrease in mid-calf muscle density was associated with a trend towards greater likelihood of experiencing a fall (OR 1.13; 95% CI 1.00, 1.29 per SD lower) and significantly greater likelihood of multiple falls (1.61; 1.16, 2.23). Higher muscle density was not associated with total hip aBMD, and was associated with lower lumbar spine aBMD (B = -0.003; 95% CI -0.005, -0.001 per mg/cm3) and higher proximal cortical vBMD (0.74; 0.20, 1.28) at the radius. At the tibia, muscle density was positively associated with distal total and trabecular vBMD, and proximal total and cortical vBMD, cortical thickness, cortical area and stress-strain index (all P < 0.05). Only moderate/vigorous (%) intensity physical activity, not sedentary time or light activity, was associated with higher mid-calf muscle density (0.086; 0.034, 0.138).CONCLUSIONS: Lower mid-calf muscle density is independently associated with higher likelihood for multiple incident falls and appears to have localised negative effects on bone structure in older adults.
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| 9. |
- Ebeling, Peter R., et al.
(author)
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The Efficacy and Safety of Vertebral Augmentation : A Second ASBMR Task Force Report
- 2019
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In: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 34:1, s. 3-21
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Journal article (peer-reviewed)abstract
- Vertebral augmentation is among the current standards of care to reduce pain in patients with vertebral fractures (VF), yet a lack of consensus regarding efficacy and safety of percutaneous vertebroplasty and kyphoplasty raises questions on what basis clinicians should choose one therapy over another. Given the lack of consensus in the field, the American Society for Bone and Mineral Research (ASBMR) leadership charged this Task Force to address key questions on the efficacy and safety of vertebral augmentation and other nonpharmacological approaches for the treatment of pain after VF. This report details the findings and recommendations of this Task Force. For patients with acutely painful VF, percutaneous vertebroplasty provides no demonstrable clinically significant benefit over placebo. Results did not differ according to duration of pain. There is also insufficient evidence to support kyphoplasty over nonsurgical management, percutaneous vertebroplasty, vertebral body stenting, or KIVA®. There is limited evidence to determine the risk of incident VF or serious adverse effects (AE) related to either percutaneous vertebroplasty or kyphoplasty. No recommendation can be made about harms, but they cannot be excluded. For patients with painful VF, it is unclear whether spinal bracing improves physical function, disability, or quality of life. Exercise may improve mobility and may reduce pain and fear of falling but does not reduce falls or fractures in individuals with VF. General and intervention-specific research recommendations stress the need to reduce study bias and address methodological flaws in study design and data collection. This includes the need for larger sample sizes, inclusion of a placebo control, more data on serious AE, and more research on nonpharmacologic interventions. Routine use of vertebral augmentation is not supported by current evidence. When it is offered, patients should be fully informed about the evidence. Anti-osteoporotic medications reduce the risk of subsequent vertebral fractures by 40–70%.
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| 10. |
- Nguyen, Hanh H., et al.
(author)
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AFFnet - a deep convolutional neural network for the detection of atypical femur fractures from anteriorposterior radiographs
- 2024
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In: Bone. - 8756-3282 .- 1873-2763. ; , s. 117215-117215
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Journal article (peer-reviewed)abstract
- Despite well-defined criteria for radiographic diagnosis of atypical femur fractures (AFFs), missed and delayed diagnosis is common. An AFF diagnostic software could provide timely AFF detection to prevent progression of incomplete or development of contralateral AFFs. In this study, we investigated the ability for an artificial intelligence (AI)-based application, using deep learning models (DLMs), particularly convolutional neural networks (CNNs), to detect AFFs from femoral radiographs. A labelled Australian dataset of pre-operative complete AFF (cAFF), incomplete AFF (iAFF), typical femoral shaft fracture (TFF), and non-fractured femoral (NFF) X-ray images in anterior-posterior view were used for training (N = 213, 49, 394, 1359, respectively). An AFFnet model was developed using a pretrained (ImageNet dataset) ResNet-50 backbone, and a novel Box Attention Guide (BAG) module to guide the model's scanning patterns to enhance its learning. All images were used to train and internally test the model using a 5-fold cross validation approach, and further validated by an external dataset. External validation of the model's performance was conducted on a Sweden dataset comprising 733 TFF and 290 AFF images. Precision, sensitivity, specificity, F1-score and AUC were measured and compared between AFFnet and a global approach with ResNet-50. Excellent diagnostic performance was recorded in both models (all AUC >0.97), however AFFnet recorded lower number of prediction errors, and improved sensitivity, F1-score and precision compared to ResNet-50 in both internal and external testing. Sensitivity in the detection of iAFF was higher for AFFnet than ResNet-50 (82 % vs 56 %). In conclusion, AFFnet achieved excellent diagnostic performance on internal and external validation, which was superior to a pre-existing model. Accurate AI-based AFF diagnostic software has the potential to improve AFF diagnosis, reduce radiologist error, and allow urgent intervention, thus improving patient outcomes.
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