| 1. |
- Cheng, Lan, et al.
(författare)
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Sex differences in the longitudinal associations between body composition and bone stiffness index in European children and adolescents
- 2020
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Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 131
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Tidskriftsartikel (refereegranskat)abstract
- Fat mass (FM) and fat free mass (FFM) may influence bone health differentially. However, existing evidences on associations between FM, FFM and bone health are inconsistent and vary according to sex and maturity. The present study aims to evaluate longitudinal associations between FM, FFM and bone stiffness index (SI) among European children and adolescents with 6 years follow-up. A sample of 2468 children from the IDEFICS/I.Family was included, with repeated measurements of SI using calcaneal quantitative ultrasound, body composition using skinfold thickness, sedentary behaviors and physical activity using self-administrated questionnaires. Regression coefficients (β) and 99%-confidence intervals (99% CI) were calculated by sex-specified generalized linear mixed effects models to analyze the longitudinal associations between FM and FFM z-scores (zFM and zFFM) and SI percentiles, and to explore the possible interactions between zFM, zFFM and maturity. Baseline zFFM was observed to predict the change in SI percentiles in both boys (β = 4.57, 99% CI: 1.36, 7.78) and girls (β = 3.42, 99% CI: 0.05, 6.79) after 2 years. Moreover, baseline zFFM (β = 8.72, 99% CI: 3.18, 14.27 in boys and β = 5.89, 99% CI: 0.34, 11.44 in girls) and the change in zFFM (β = 6.58, 99% CI: 0.83, 12.34 in boys and β = 4.81, 99% CI: -0.41, 10.02 in girls) were positively associated with the change in SI percentiles after 6 years. In contrast, a negative association was observed between the change in zFM and SI percentiles in boys after 6 years (β = -3.70, 99% CI: -6.99, -0.42). Besides, an interaction was observed between the change in zFM and menarche on the change in SI percentiles in girls at 6 years follow-up (p = .009), suggesting a negative association before menarche while a positive association after menarche. Our findings support the existing evidences for a positive relationship between FFM and SI during growth. Furthermore, long-term FM gain was inversely associated with SI in boys, whereas opposing associations were observed across menarche in girls.
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| 2. |
- Dou, Zelong, et al.
(författare)
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Rat perichondrium transplanted to articular cartilage defects forms articular-like, hyaline cartilage
- 2021
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Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 151
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Perichondrium autotransplants have been used to reconstruct articular surfaces destroyed by infection or trauma. However, the role of the transplanted perichondrium in the healing of resurfaced joints have not been investigated.DESIGN: Perichondrial and periosteal tissues were harvested from rats hemizygous for a ubiquitously expressed enhanced green fluorescent protein (EGFP) transgene and transplanted into full-thickness articular cartilage defects at the trochlear groove of distal femur in wild-type littermates. As an additional control, cartilage defects were left without a transplant (no transplant control). Distal femurs were collected 3, 14, 56, 112 days after surgery.RESULTS: Tracing of transplanted cells showed that both perichondrium and periosteum transplant-derived cells made up the large majority of the cells in the regenerated joint surfaces. Perichondrium transplants contained SOX9 positive cells and with time differentiated into a hyaline cartilage that expanded and filled out the defects with Col2a1-positive and Col1a1-negative chondrocytes and a matrix rich in proteoglycans. At later timepoints the cartilaginous perichondrium transplants were actively remodeled into bone at the transplant-bone interface and at post-surgery day 112 EGFP-positive perichondrium cells at the articular surface were positive for Prg4. Periosteum transplants initially lacked SOX9 expression and despite a transient increase in SOX9 expression and chondrogenic differentiation, remained Col1a1 positive, and were continuously thinning as periosteum-derived cells were incorporated into the subchondral compartment.CONCLUSIONS: Perichondrium and periosteum transplanted to articular cartilage defects did not just stimulate regeneration but were themselves transformed into cartilaginous articular surfaces. Perichondrium transplants developed into an articular-like, hyaline cartilage, whereas periosteum transplants appeared to produce a less resilient fibro-cartilage.
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| 3. |
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| 4. |
- Fratzl-Zelman, N., et al.
(författare)
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Bone material properties and response to teriparatide in osteoporosis due to WNT1 and PLS3 mutations
- 2021
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 146
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Tidskriftsartikel (refereegranskat)abstract
- Context: Patients with osteoporosis-associated WNT1 or PLS3 mutations have unique bone histomorphometric features and osteocyte-specific hormone expression patterns. Objective: To investigate the effects of WNT1 and PLS3 mutations on bone material properties. Design: Transiliac bone biopsies were evaluated by quantitative backscattered electron imaging, immunohistochemistry, and bone histomorphometry. Setting: Ambulatory patients. Patients: Three pediatric and eight adult patients with WNT1 or PLS3 mutations. Intervention: Bone mineralization density distribution and osteocyte protein expression was evaluated in 11 patients and repeated in six patients who underwent repeat biopsy after 24 months of teriparatide treatment. Main outcome measure: Bone mineralization density distribution and protein expression. Results: Children with WNT1 or PLS3 mutations had heterogeneous bone matrix mineralization, consistent with bone modeling during growth. Bone matrix mineralization was homogenous in adults and increased throughout the age spectrum. Teriparatide had very little effect on matrix mineralization or bone formation in patients with WNT1 or PLS3 mutations. However, teriparatide decreased trabecular osteocyte lacunae size and increased trabecular bone FGF23 expression. Conclusion: The contrast between preserved bone formation with heterogeneous mineralization in children and low bone turnover with homogenous bone mineral content in adults suggests that WNT1 and PLS3 have differential effects on bone modeling and remodeling. The lack of change in matrix mineralization in response to teriparatide, despite clear changes in osteocyte lacunae size and protein expression, suggests that altered WNT1 and PLS3 expression may interfere with coupling of osteocyte, osteoblast, and osteoclast function. Further studies are warranted to determine the mechanism of these changes.
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| 5. |
- Frysz, Monika, et al.
(författare)
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The influence of adult hip shape genetic variants on adolescent hip shape : Findings from a population-based DXA study
- 2021
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Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 143
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Hip shape is a well-recognized risk factor for hip osteoarthritis (OA) and hip fracture. We aimed to investigate whether the genetic variants known to be associated with adult hip shape were also associated with adolescent hip shape.Methods: Hip DXA scans, obtained in offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) at two time points (mean ages 13.8 and 17.8 years), were used to quantify hip morphology using a 53-point Statistical Shape Model (SSM). Principal component analysis was used to generate hip shape modes (HSMs). Genetic variants which had previously shown genome-wide significant association with specific HSMs in adults were tested for association with the same HSMs in adolescents (at each timepoint separately) using SNPTEST v2.Results: Complete genotypic and phenotypic data were available for 3550 and 3175 individuals at 14 and 18 years, respectively. The strongest evidence for association with adolescent hip shape was for a variant located near SOX9 (rs2158915) with consistent effects across both time points for HSM1 (age 14: beta -0.05, p = 9.9 x 10(-8); age 18: -0.05, p = 3.3 x 10(-6)) and HSM5 (age 14: beta -0.07, p = 1.6 x 10(-4); age 18: -0.1, p = 2.7 x 10(-6)). There was also strong evidence of association between rs10743612 (near PTHLH) and HSM1 (age 14: 0.05, p = 1.1 x 10(-5); age 18: 0.04, p = 0.003) and between rs6537291 (near HHIP) and HSM2 (age 14: -0.06, p = 0.001; age 18: -0.07, p = 0.001) across both time points. The genes with the strongest associations with hip shape in adolescents, (SOX9, PTHLH and HHIP) are known to be involved in endochondral bone formation. HSM1 indicates narrower aspect ratio of the upper femur, whereas both HSM2 and HSM5 reflect variation in the femoral head size and femoral neck width, features previously found to be related to the risk of OA in later life. The SOX9 locus has previously been found to associate with increased risk of hip fracture.Conclusion: In conclusion, variants implicated in endochondral bone formation appear to consistently influence hip shape between adolescence and adulthood, including those aspects related to risk of hip OA and/or fracture in later life.
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| 6. |
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| 7. |
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| 8. |
- Grassi, Lorenzo, et al.
(författare)
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Validation of 3d finite element models from simulated Dxa images for Biofidelic simulations of sideways fall impact to the hip
- 2020
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 142
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Tidskriftsartikel (refereegranskat)abstract
- Computed tomography (CT)-derived finite element (FE) models have been proposed as a tool to improve the current clinical assessment of osteoporosis and personalized hip fracture risk by providing an accurate estimate of femoral strength. However, this solution has two main drawbacks, namely: (i) 3D CT images are needed, whereas 2D dual-energy x-ray absorptiometry (DXA) images are more generally available, and (ii) quasi-static femoral strength is predicted as a surrogate for fracture risk, instead of predicting whether a fall would result in a fracture or not. The aim of this study was to combine a biofidelic fall simulation technique, based on 3D computed tomography (CT) data with an algorithm that reconstructs 3D femoral shape and BMD distribution from a 2D DXA image. This approach was evaluated on 11 pelvis-femur constructs for which CT scans, ex vivo sideways fall impact experiments and CT-derived biofidelic FE models were available. Simulated DXA images were used to reconstruct the 3D shape and bone mineral density (BMD) distribution of the left femurs by registering a projection of a statistical shape and appearance model with a genetic optimization algorithm. The 2D-to-3D reconstructed femurs were meshed, and the resulting FE models inserted into a biofidelic FE modeling pipeline for simulating a sideways fall. The median 2D-to-3D reconstruction error was 1.02 mm for the shape and 0.06 g/cm3 for BMD for the 11 specimens. FE models derived from simulated DXAs predicted the outcome of the falls in terms of fracture versus non-fracture with the same accuracy as the CT-derived FE models. This study represents a milestone towards improved assessment of hip fracture risk based on widely available clinical DXA images.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
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| 13. |
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| 14. |
- Liphardt, Anna-Maria, et al.
(författare)
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Changes in mechanical loading affect arthritis-induced bone loss in mice.
- 2020
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 131
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Tidskriftsartikel (refereegranskat)abstract
- Arthritis induces bone loss by inflammation-mediated disturbance of bone homeostasis. On the other hand, pain and impaired locomotion are highly prevalent in arthritis and result in reduced general physical activity and less pronounced mechanical loading. Bone is affected by mechanical loading, directly through impact with the ground during movement and indirectly through muscular activity. Mechanical loading in its physiological range is essential for maintaining bone mass, whereas disuse leads to bone loss. The aim of this study was to investigate the impact of mechanical loading on periarticular bone as well as inflammation during arthritis. Mechanical loading was either blocked by botulinum neurotoxin A (Botox) injections before induction of arthritis, or enhanced by cyclic compressive loading, three times per week during arthritis induction. Arthritis was verified and evaluated histologically. Trabecular and cortical bone mass were investigated using micro-computed tomography (μCT), subchondral osteoclastogenesis and bone turnover was assessed by standard methods. Inhibition of mechanical loading enhanced arthritis-induced bone loss while it did not affect inflammation. In contrast, enhanced mechanical loading mitigated arthritis-induced bone loss. Furthermore, the increase in bone resorption markers by arthritis was partly blocked by mechanical loading. In conclusion, enhanced arthritic bone loss after abrogation of mechanical loading suggests that muscle forces play an essential role in preventing arthritic bone loss. In accordance, mechanical loading of the arthritic joints inhibited bone loss, emphasizing that weight bearing activities may have the potential to counteract arthritis-mediated bone loss.
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| 15. |
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| 16. |
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| 17. |
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| 18. |
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| 19. |
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| 20. |
- Sanchez-Duffhues, Gonzalo, et al.
(författare)
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Bone morphogenetic protein receptors : Structure, function and targeting by selective small molecule kinase inhibitors
- 2020
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 138
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Forskningsöversikt (refereegranskat)abstract
- Bone morphogenetic proteins (BMPs) are secreted cytokines that control the fate and function of many different cell types. They exert their cellular responses via heteromeric complexes of specific BMP type I and type II serine/threonine kinase receptors, e.g. BMPRIA and BMPRII. Three type II and four type I receptors, also termed activin receptor-like kinases (ALKs), have been identified. The constitutively active type II kinase phosphorylates the type I receptor, which upon activation initiates intracellular signaling by phosphorylating SMAD effectors. Auxiliary cell surface receptors without intrinsic enzymatic motifs, such as Endoglin and Repulsive guidance molecules (RGM), can fine-tune signaling by regulating the interaction of the BMP ligands with the BMPRs. The functional annotation of the BMPR encoding genes has helped to understand underlying mechanisms of diseases in which these genes are mutated. Loss of function mutations in BMPRII, Endoglin or RGMc are causally linked to pulmonary arterial hypertension, hereditary hemorrhagic telangiectasia and juvenile hemochromatosis, respectively. In contrast, gain of function mutations in ACVR1, encoding ALK2, are linked to Fibrodysplasia ossificans progressiva and diffuse intrinsic pontine glioma. Here, we discuss BMPR identification, structure and function in health and disease. Moreover, we highlight the therapeutic promise of small chemical compounds that act as selective BMPR kinase inhibitors to normalize overactive BMPR signaling.
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| 21. |
- Stattin, Karl, et al.
(författare)
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Fracture risk across a wide range of physical activity levels, from sedentary individuals to elite athletes.
- 2021
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Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 153
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine how physical activity is associated with risk of different fracture outcomes across the full range of physical activity.METHODS: By combining information from three cohort studies and using generalized structural equation modelling, we estimated a continuous unitless latent variable reflecting physical activity that ranged from sedentary through elite athlete levels. Associations between physical activity and fracture outcomes were assessed with proportional hazards regression using restricted cubic splines with the mean physical activity (corresponding to 20-40 min walking or bicycling/day or 2-3 h exercise/week) as reference.RESULTS: Among 63,980 men and women (49-68 years) and during 13 years of follow-up, 8506 fractures occurred, including 2164 distal forearm, 779 proximal humerus, 346 clinical spine, and 908 hip fractures. Both lower and higher physical activity was associated with higher risk of any fracture compared to the mean. Physical activity at 1 standard deviation (SD) below the mean, corresponding to walking/bicycling <20 min/day or exercising <1-1 h/week, was associated with a lower risk of distal forearm fracture (hazard ratio [HR]: 0.92, 95% confidence interval [CI]: 0.85-0.99) and higher risk of hip fracture (HR: 1.24, 95% CI: 1.13-1.37), but no associations were seen above the mean physical activity level for these fractures. Physical activity was not associated with proximal humerus fracture but had a possible U-shaped association with clinical spine fracture.CONCLUSION: Physical activity was non-linearly associated with fracture risk and the association differed across fracture sites. Up to 2-3 h weekly exercise is beneficial for the prevention of hip fracture but may increase the risk of distal forearm fracture.
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| 22. |
- Söreskog, Emma, et al.
(författare)
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Risk of major osteoporotic fracture after first, second and third fracture in Swedish women aged 50 years and older
- 2020
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 134
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Tidskriftsartikel (refereegranskat)abstract
- Background: Osteoporosis affects approximately one in five European women and leads to fragility fractures, which result in poor health, social and economic consequences. Fragility fractures are a strong risk factor for subsequent major osteoporotic fracture (MOF), with risk of MOF being elevated in the 1–2 years following an earlier fracture, a concept described as “imminent risk”. This study examines risk of subsequent MOF in patients with one, two or three prior fractures by age and type of fracture. Methods: In this retrospective, observational cohort study, Swedish women aged ≥50 years with ≥1 any clinical fragility fracture between July 1, 2006 and December 31, 2012 were identified from Sweden's National Patient Register. Each patient was age- and sex-matched to three controls without history of fracture. Group 1 women included those with one fragility fracture during the study period; Group 2 included those with two fragility fractures; and Group 3 included those with three fragility fractures. “Index fracture” was defined as the first fracture during the study period for Group 1; the second for Group 2; and the third for Group 3. Patients in each cohort and matched controls were followed for up to 60 months or until subsequent MOF (hip, vertebra, forearm, humerus), death or end of data availability. Results: 231,769 women with at least one fracture were included in the study and therefore constituted Group 1; of these, 39,524 constituted Group 2 and of those, 7656 constituted Group 3. At five years, cumulative incidence of subsequent MOF was higher in patients with a history of fracture as compared to controls (Group 1: 20.7% vs 12.3%; Group 2: 32.0% vs 15.3%). Three-year cumulative incidence for Group 3 was 12.1% (vs 10.7% for controls). After adjusting for baseline covariates, risk of subsequent MOF was highest within 0–24 months following an index fracture, then decreased but remained elevated as compared to controls. Having two prior fractures, vertebral fractures and younger age at time of index fracture were associated with greater relative risk. Conclusions: Women with a history of osteoporotic fracture are at increased risk of subsequent fracture, which is highest during the first 24 months following a fracture. Younger women and those with vertebral fractures are at greatest relative risk, suggesting that treatment should target these patients and be timely enough to impact the period of imminent risk.
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| 23. |
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| 24. |
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| 25. |
- Wallin, Maria, et al.
(författare)
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Blood cadmium is associated with increased fracture risk in never-smokers - results from a case-control study using data from the Malmö Diet and Cancer cohort
- 2024
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Ingår i: BONE. - 8756-3282 .- 1873-2763. ; 179
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several studies have shown associations between cadmium (Cd) exposure and an increased risk of fractures. However, the size of the risk is still unclear and proper adjustment for smoking is a challenge. The aim of this study was to quantify the association between dietary cadmium measured in blood and fracture risk in the general Swedish population through a large population-based case-control study in never-smokers.Methods: The study included 2113 incident cases with osteoporosis-related fractures and the same number of age- and sex-matched controls in never-smokers from the Swedish population-based Malmö Diet and Cancer study cohort. Cd in blood (B-Cd) was analyzed at baseline (1991-1996). Incident osteoporosis-related fractures (of the hip, distal radius, and proximal humerus) up to the year 2014 were identified using the National Patient Register. Associations between B-Cd and fractures were analyzed using logistic regression.Results: Median B-Cd was 0.22 mu g/L (P25 = 0.16, P75 = 0.31) among 2103 cases and 0.21 (P25 = 0.15, P75 = 0.30) among 2105 controls. The risk of fracture was significantly increased (OR 1.58; 95 % confidence interval 1.08-2.31, per mu g/L of B-Cd), after adjustment for age, sex, BMI, physical activity, and fiber consumption. In analyses by cadmium quartiles, the OR increased monotonically and was significant in the highest quartile of B-Cd (for B-Cd > 0.31 versus B-Cd < 0.15 mu g/L; OR 1.21; 95 % confidence interval 1.01-1.45).Conclusion: Even modestly increased blood cadmium in never-smokers is associated with increased risk of incident osteoporosis-related fractures.
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| 26. |
- Wallin, Maria, et al.
(författare)
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Low-level cadmium exposure is associated with decreased cortical thickness, cortical area and trabecular bone volume fraction in elderly men: The MrOS Sweden study.
- 2021
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Ingår i: Bone. - : Elsevier BV. - 1873-2763 .- 8756-3282. ; 43
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Tidskriftsartikel (refereegranskat)abstract
- It is well known that high-level exposure to cadmium can cause bone disease such as osteoporosis, osteomalacia and fractures. However, the effect of low-level exposure, as found in the general population (mainly derived from diet and smoking), has only been assessed recently. The aim of this study was to examine if cadmium exposure in the general Swedish population causes other bone changes than decreased areal bone mineral density as measured by traditional DXA technology, e.g. changes in microstructure and geometry, such as cortical thickness or area, cortical porosity and trabecular bone volume. The study population consisted of 444 men, aged 70-81years at inclusion year 2002-2004, from the Swedish cohort of the Osteoporotic Fractures in Men Study (MrOS). Cadmium was analyzed in baseline urine samples (UCd). Different parameters of bone geometry and microstructure were measured at the distal tibia at follow-up in 2009, including examination with high-resolution peripheral quantitative computed tomography (HR-pQCT). Associations between bone parameters and UCd in tertiles were estimated in multivariable analyses, including potential confounding factors (age, smoking, BMI, and physical activity). We found significant associations between UCd and several bone geometry or microstructure parameters, with 9% lower cortical thickness (p=0.03), 7% lower cortical area (p=0.04), and 5% lower trabecular bone volume fraction (p=0.02) in the third tertile of UCd, using the first tertile as the reference. Furthermore, significant negative associations were found between log-transformed UCd and cortical thickness, cortical area, trabecular number and trabecular bone volume fraction, and a significant positive association with trabecular separation. The results indicate that low-level Cd exposure in the general population has negative effects on both cortical and trabecular bone.
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| 27. |
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| 28. |
- Whyte, Michael P., et al.
(författare)
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Persistent idiopathic hyperphosphatasemia from bone alkaline phosphatase in a healthy boy
- 2020
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Ingår i: Bone. - : ELSEVIER SCIENCE INC. - 8756-3282 .- 1873-2763. ; 138
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Tidskriftsartikel (refereegranskat)abstract
- Alkaline phosphatase (ALP) in humans comprises a family of four cell-surface phosphomonoester phosphohydrolase isozymes. Three genes separately encode the "tissue-specific" ALPs whereas the fourth gene encodes ubiquitous homodimeric "tissue-nonspecific" ALP (TNSALP) richly expressed in bone, liver, kidney, and developing teeth. TNSALP monomers have five putative N-linked glycosylation sites where different post-translational modifications account for this isozymes distinctive physicochemical properties in different organs. Three bone-derived TNSALP (BALP) isoforms (B/I, B1, and B2) are present in healthy serum, whereas a fourth BALP isoform (Blx) can circulate in chronic kidney disease. Herein, we report a healthy boy with persistent hyperphosphatasemia due to BALP levels two- to threefold higher than age-appropriate reference values. Highperformance liquid chromatography, electrophoresis, heat inactivation, catalysis inhibition, and polyethylene glycol precipitation revealed increased serum B/I, B1, and B2 differing from patterns found in skeletal diseases. BA was similar to 23-fold elevated. Absence of mental retardation and physical stigmata excluded Mabry syndrome, the ALP-anchoring disorder causing hyperphosphatasemia. Routine biochemical studies indicated intact mineral homeostasis. Serum N-terminal propeptide of type I procollagen (P1NP) level was normal, but C-terminal crosslinking telopeptide of type I collagen (CTX) level was elevated. However, radiological studies showed no evidence for a generalized skeletal disturbance. Circulating pyridoxal 5-phosphate, a TNSALP natural substrate, was not low despite the laboratory hyperphosphatasemia, thereby suggesting BALP phosphohydrolase activity was not elevated endogenously. Mutation analysis of the ALPL gene encoding TNSALP revealed no defect. His non-consanguineous healthy parents had serum total ALP activity and BALP protein levels that were normal. Our patients sporadic idiopathic hyperphosphatasemia could reflect altered post-translational modification together with increased expression and/or impaired degradation of BALP.
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| 29. |
- Wändell, Per, et al.
(författare)
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Distal forearm fractures in immigrant groups : A national Swedish study
- 2020
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 138
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim was to analyse risk of forearm fractures in first- and second-generation immigrants to Sweden. Methods: A nationwide study of individuals 20 years of age and older was conducted. Forearm fractures were defined as at least one registered diagnosis in the National Patient Register between January 1, 1998 and December 31, 2012. Cox regression analysis was used to estimate the relative risk (hazard ratios (HR) with 95% confidence intervals (CI)) of incident forearm fractures compared to Swedish-born individuals, or in second-generation immigrant groups relative to individuals with Swedish-born parents. Cox regression models were stratified by sex and adjusted for age, sociodemographic status, and co-morbidities. Results: A total of 5,953,764 individuals were included in the first-generation study (2,861,256 men, and 3,092,508 women), and a forearm fracture was registered in 166,955 individuals (2.8%). The second-generation study included 4,656,023 individuals (2,368,585 men, and 2,287,438 women) with a registered forearm fracture in 111,576 individuals (2.4%). Fully adjusted HRs showed marginally lower risks when all immigrants were studied, for first-generation men 0.95 (95% CI 0.92–0.98) and women 0.95 (95% CI 95 0.92–0.97), and for second-generation men 0.93 (95% CI 0.90–0.97) and women 0.90 (95% CI 0.88–0.93). An increased risk was found among some first-generation immigrant men, especially in men from the Middle East. Conclusions: We observed a marginally lower overall risk of fractures among immigrants, but with differences among the immigrant groups.
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| 30. |
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| 31. |
- Jensen, Vivi F.H., et al.
(författare)
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Changes in bone mass associated with obesity and weight loss in humans : Applicability of animal models
- 2021
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Ingår i: Bone. - : Elsevier BV. - 8756-3282. ; 145
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Forskningsöversikt (refereegranskat)abstract
- The implications of obesity and weight loss for human bone health are not well understood. Although the bone changes associated with weight loss are similar in humans and rodents, that is not the case for obesity. In humans, obesity is generally associated with increased bone mass, an outcome which is exacerbated by advanced age and menopause. In rodents, by contrast, bone mass decreases in proportion to severity and duration of obesity, and is influenced by sex, age and mechanical load. Despite these discrepancies, rodents are frequently used to model the situation in humans. In this review, we summarise the existing knowledge of the effects of obesity and weight loss on bone mass in humans and rodents, focusing on the translatability of findings from animal models. We then describe how animal models should be used to broaden the understanding of the relationship between obesity, weight loss, and skeletal health in humans. Specifically, we highlight the aspects of study design that should be considered to optimise translatability of the rodent models of obesity and weight loss. Notably, the sex, age, and nutritional status of the animals should ideally match those of interest in humans. With these caveats in mind, and depending on the research question asked, our review underscores that animal models can provide valuable information for obesity and weight-management research.
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| 32. |
- Lauterlein, Jens Jacob L., et al.
(författare)
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Serum sclerostin and glucose homeostasis : No association in healthy men. Cross-sectional and prospective data from the EGIR-RISC study
- 2021
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Ingår i: Bone. - : Elsevier BV. - 8756-3282. ; 143
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Sclerostin, an inhibitor of bone formation, has emerged as a potential negative regulator of glucose homeostasis. We aimed to investigate if serum sclerostin associates with insulin sensitivity, beta cell function, prediabetes or metabolic syndrome in healthy men. Materials and methods: Serum sclerostin was measured in basal and insulin-stimulated samples from 526 men without diabetes from the RISC cohort study. An OGTT was performed at baseline and after 3 years. An IVGTT and a hyperinsulinaemic-euglycaemic clamp were performed at baseline. Insulin sensitivity was estimated by the oral glucose sensitivity index (OGIS) and the M-value relative to insulin levels. Beta cell function was assessed by the acute and total insulin secretion (ISRtot) and by beta cell glucose sensitivity. Results: Serum sclerostin levels correlated positively with age but were similar in individuals with (n = 69) and without (n = 457) prediabetes or the metabolic syndrome. Serum sclerostin was associated with measures of neither insulin sensitivity nor beta cell function at baseline in age-adjusted analyses including all participants. However, baseline serum sclerostin correlated inversely with OGIS at follow-up in men without prediabetes (B: −0.29 (−0.57, −0.01) p = 0.045), and inversely with beta cell glucose sensitivity in men with prediabetes (B: −13.3 (−26.3, −0.2) p = 0.046). Associations between serum sclerostin and 3-year changes in measures of glucose homeostasis were not observed. Acute hyperinsulinemia suppressed serum sclerostin (p = 0.02), and this reduction correlated with OGIS and ISRtot. Conclusions: Overall, serum sclerostin was not associated with prediabetes, insulin sensitivity or insulin secretion in healthy men. The inverse relationship between serum sclerostin and insulin sensitivity at follow-up was weak and likely not of clinical relevance. The ability of insulin to reduce sclerostin, possibly promoting bone formation, needs to be clarified.
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| 33. |
- Micheletti, Chiara, et al.
(författare)
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Bone structure and composition in a hyperglycemic, obese, and leptin receptor-deficient rat: Microscale characterization of femur and calvarium
- 2023
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Ingår i: Bone. - 8756-3282. ; 172
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic abnormalities, such as diabetes mellitus and obesity, can impact bone quantity and/or bone quality. In this work, we characterize bone material properties, in terms of structure and composition, in a novel rat model with congenic leptin receptor (LepR) deficiency, severe obesity, and hyperglycemia (type 2 diabetes-like condition). Femurs and calvaria (parietal region) from 20-week-old male rats are examined to probe bones formed both by endochondral and intramembranous ossification. Compared to the healthy controls, the LepR-deficient animals display significant alterations in femur microarchitecture and in calvarium morphology when analyzed by micro-computed X-ray tomography (micro-CT). In particular, shorter femurs with reduced bone volume, combined with thinner parietal bones and shorter sagittal suture, point towards a delay in the skeletal development of the LepR-deficient rodents. On the other hand, LepR-deficient animals and healthy controls display analogous bone matrix composition, which is assessed in terms of tissue mineral density by micro-CT, degree of mineralization by quantitative backscattered electron imaging, and various metrics extrapolated from Raman hyperspectral images. Some specific microstructural features, i.e., mineralized cartilage islands in the femurs and hyper-mineralized areas in the parietal bones, also show comparable distribution and characteristics in both groups. Overall, the altered bone microarchitecture in the LepR-deficient animals indicates compromised bone quality, despite the normal bone matrix composition. The delayed development is also consistent with observations in humans with congenic Lep/LepR deficiency, making this animal model a suitable candidate for translational research.
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| 34. |
- Nguyen, Jacqueline, et al.
(författare)
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CYLD, a mechanosensitive deubiquitinase, regulates TGFβ signaling in load-induced bone formation
- 2020
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Ingår i: Bone. - : Elsevier BV. - 8756-3282. ; 131
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Tidskriftsartikel (refereegranskat)abstract
- Many signaling pathways involved in bone homeostasis also participate in the anabolic response of bone to mechanical loading. For example, TGFβ signaling coordinates the maintenance of bone mass and bone quality through its effects on osteoblasts, osteoclasts, and osteocytes. TGFβ signaling is also essential for the mechanosensitive formation of new bone. However, the mechanosensitive mechanisms controlling TGFβ signaling in osteocytes remain to be determined, particularly those that integrate TGFβ signaling with other early responses to mechanical stimulation. Here, we used an in vivo mouse hindlimb loading model to identify mechanosensitive molecules in the TGFβ pathway, and MLO-Y4 cells to evaluate their interactions with the prostaglandin E2 (PGE2) pathway, which is well-known for its rapid response to mechanical stimulation and its role in bone anabolism. Although mRNA levels for several TGFβ ligands, receptors, and effectors were unchanged, the level of phosphorylated Smad2/3 (pSmad2/3) was reduced in tibial bone as early as 3 h after early mechanical stimulation. We found that PGE2 and its receptor, EP2, repress pSmad2/3 levels and transactivation of Serpine1 in osteocytes. PGE2 and EP2 control the level of pSmad2/3 through a proteasome-dependent mechanism that relies on the deubiquitinase CYLD. CYLD protein levels were also reduced in the tibiae within 3 h of mechanical loading. Using CYLD-deficient mice, we found that CYLD is required for the rapid load-mediated repression of pSmad2/3 and for load-induced bone formation. These data introduce CYLD as a mechanosensitive deubiquitinase that participates in the prostaglandin-dependent repression of TGFβ signaling in osteocytes.
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| 35. |
- Pierantoni, Maria, et al.
(författare)
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Muscular loading affects the 3D structure of both the mineralized rudiment and growth plate at early stages of bone formation
- 2021
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Ingår i: Bone. - : Elsevier BV. - 8756-3282. ; 145
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Tidskriftsartikel (refereegranskat)abstract
- Fetal immobilization affects skeletal development and can lead to severe malformations. Still, how mechanical load affects embryonic bone formation is not fully elucidated. This study combines mechanobiology, image analysis and developmental biology, to investigate the structural effects of muscular loading on embryonic long bones. We present a novel approach involving a semi-automatic workflow, to study the spatial and temporal evolutions of both hard and soft tissues in 3D without any contrast agent at micrometrical resolution. Using high-resolution phase-contrast-enhanced X-ray synchrotron microtomography, we compare the humeri of Splotch-delayed embryonic mice lacking skeletal muscles with healthy littermates. The effects of skeletal muscles on bone formation was studied from the first stages of mineral deposition (Theiler Stages 23 and 24) to just before birth (Theiler Stage 27). The results show that muscle activity affects both growth plate and mineralized regions, especially during early embryonic development. When skeletal muscles were absent, there was reduced mineralization, altered tuberosity size and location, and, at early embryonic stages, decreased chondrocyte density, size and elongation compared to littermate controls. The proposed workflow enhances our understanding of mechanobiology of early bone formation and could be implemented for the study of other complex biological tissues.
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| 36. |
- Schini, M., et al.
(författare)
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Increased fracture risk in Parkinson's disease - An exploration of mechanisms and consequences for fracture prediction with FRAX
- 2023
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Ingår i: Bone. - : Elsevier BV. - 8756-3282. ; 168
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Tidskriftsartikel (refereegranskat)abstract
- The relative contributions of factors such as muscle strength, falls risk and low bone mineral density (BMD) to increased fracture risk in Parkinson's Disease (PD) were examined in an analysis of 5212 community-dwelling women age 75 years or more recruited to a randomised, double-blind, placebo-controlled study of the oral bisphosphonate, clodronate. Similar number of PD and non-PD subjects received treatment. Each participant had measurements of hip and forearm BMD, muscle strength (hand grip strength and maximum isometric quadriceps strength), ability in the sit-to-stand test, and postural stability. Incident radiographic and/or surgically verified fractures, and deaths, were recorded over an average follow-up of 3.8 years. A diagnosis of PD was made if it was self-reported and appropriate medication was recorded at the study entry. 47 of the women (0.9 %) had a diagnosis of PD at baseline. They were of similar age to those without PD, but reported higher disability scores and lower quality of life. While BMD at the forearm and hip regions was lower in PD, this only reached statistical significance at the femoral neck (0.61 +/- 0.12 vs 0.65 +/- 0.12 g/cm2, p = 0.037). Right hand grip strength was non-significantly lower in PD, but maximum right quadriceps strength was much reduced (96.9 +/- 49.3 vs 126.3 +/- 59.2 N, p = 0.003). Eleven (23.4 %) of the women with PD sustained 12 fractures, while 609 women (11.8 %) without PD sustained 742 osteoporotic fractures. The risk of osteoporotic fracture associated with PD was 2.24-fold higher in women with PD (Cox-regression HR 2.24, 95 % CI 1.23-4.06) and this remained high when adjusted for death as a competing risk (2.17, 95 % CI 1.17-4.01, p = 0.013). Following adjustment for femoral neck BMD, PD remained a significant predictor of fracture (HR 2.04, 1.12-3.70, p = 0.020). Entering PD as a risk variable using the rheumatoid arthritis input as a surrogate resulted in a reduction in PD as a FRAX-independent risk factor, particularly when BMD was included in FRAX (1.65, 95 % CI), but the relationship between PD and fracture risk appears to remain of clinical significance. The study suggests that PD may be an independent input in future iterations of FRAX, possibly due to nonskeletal components of risk such as reduced lower limb muscle strength. Introducing measures of muscle strength and performance in FRAX could also be considered.
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