Pub Date : 2025-01-23DOI: 10.1016/j.bone.2025.117394
Simone Poncioni , Kurt Lippuner , Philippe Zysset
Nonlinear homogenised finite element (hFE) models can accurately predict stiffness and strength of ultra-distal sections of the radius and tibia using in vivo HR-pQCT images. Recent findings showed good stiffness prediction at these distal sections but a limited ability to reproduce experimental strain localisation. The coarseness of voxel-based meshes reduces the computational effort at the cost of heavily simplifying the underlying geometry of the cortex, the gradient of material properties, and the resulting strain distribution. To overcome these limitations, we present a comprehensive approach to generating fully automated, smooth, and structured hexahedral meshes for HR-pQCT scans at the distal radius and tibia. This study used three datasets to validate the proposed hFE pipeline and its short-term repeatability: ex vivo 2nd generation HR-pQCT images of 21 human radii and 25 human tibiae, and 208 in vivo images from same-day repeated scans on 39 individuals. Results show high accuracy in predicting stiffness (tibia: , radius: and yield force (tibia: radius: Mesh sensitivity analysis reveals stabilisation within a 3 % error margin. Dice similarity coefficients between mesh and scanned image were and good element quality was achieved across the validation datasets (tibia: radius: Along with the improved volumetric representation of distal cortical and trabecular bone geometry and the good element quality, the new pipeline shows gains in computational performance: min for triple-stack tibia images and min for double-stack radius images, respectively. Generating structured meshes with consistent element-to-element correspondence facilitates seamless comparison between patient models or in longitudinal settings, providing an additional clinical information.
{"title":"Advancing HR-pQCT-based homogenised FE models with smooth structured hexahedral meshes","authors":"Simone Poncioni , Kurt Lippuner , Philippe Zysset","doi":"10.1016/j.bone.2025.117394","DOIUrl":"10.1016/j.bone.2025.117394","url":null,"abstract":"<div><div>Nonlinear homogenised finite element (hFE) models can accurately predict stiffness and strength of ultra-distal sections of the radius and tibia using <em>in vivo</em> HR-pQCT images. Recent findings showed good stiffness prediction at these distal sections but a limited ability to reproduce experimental strain localisation. The coarseness of voxel-based meshes reduces the computational effort at the cost of heavily simplifying the underlying geometry of the cortex, the gradient of material properties, and the resulting strain distribution. To overcome these limitations, we present a comprehensive approach to generating fully automated, smooth, and structured hexahedral meshes for HR-pQCT scans at the distal radius and tibia. This study used three datasets to validate the proposed hFE pipeline and its short-term repeatability: <em>ex vivo</em> 2nd generation HR-pQCT images of 21 human radii and 25 human tibiae, and 208 <em>in vivo</em> images from same-day repeated scans on 39 individuals. Results show high accuracy in predicting stiffness (tibia: <span><math><msup><mi>R</mi><mn>2</mn></msup><mo>=</mo><mn>0.94</mn></math></span>, radius: <span><math><msup><mi>R</mi><mn>2</mn></msup><mo>=</mo><mn>0.88</mn><mo>)</mo></math></span> and yield force (tibia: <span><math><msup><mi>R</mi><mn>2</mn></msup><mo>=</mo><mn>0.93</mn><mo>,</mo></math></span> radius: <span><math><msup><mi>R</mi><mn>2</mn></msup><mo>=</mo><mn>0.95</mn><mo>)</mo><mo>.</mo></math></span> Mesh sensitivity analysis reveals stabilisation within a <span><math><mo>±</mo></math></span> 3 % error margin. Dice similarity coefficients between mesh and scanned image were <span><math><mo>></mo><mn>0.98</mn><mo>,</mo></math></span> and good element quality was achieved across the validation datasets (tibia: <span><math><mfenced><mrow><mi>S</mi><mo>−</mo></mrow></mfenced><msub><mi>ICN</mi><mi>avg</mi></msub><mo>=</mo><mn>0.809</mn><mo>,</mo></math></span> radius: <span><math><mfenced><mrow><mi>S</mi><mo>−</mo></mrow></mfenced><msub><mi>ICN</mi><mi>avg</mi></msub><mo>=</mo><mn>0.764</mn><mo>)</mo><mo>.</mo></math></span> Along with the improved volumetric representation of distal cortical and trabecular bone geometry and the good element quality, the new pipeline shows gains in computational performance: <span><math><mfenced><mrow><mn>11.70</mn><mo>±</mo><mn>1.49</mn></mrow></mfenced></math></span> min for triple-stack tibia images and <span><math><mfenced><mrow><mn>11.00</mn><mo>±</mo><mn>0.97</mn></mrow></mfenced></math></span> min for double-stack radius images, respectively. Generating structured meshes with consistent element-to-element correspondence facilitates seamless comparison between patient models or in longitudinal settings, providing an additional clinical information.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"193 ","pages":"Article 117394"},"PeriodicalIF":3.5,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-23DOI: 10.1016/j.bone.2025.117408
Ming Ma , Yuji Zhang , Jinmin Liu , Cong Tian , Zhenkun Duan , Xingchun Huang , Bin Geng
Purpose
The correlation between serum 25-hydroxy vitamin D [(25(OH)D] and mortality in patients with osteopenia or osteoporosis remains unclear. Therefore, this study examined the relationship between serum 25(OH)D and mortality in patients with osteopenia or osteoporosis.
Methods and results
This prospective cohort study included patients with osteopenia or osteoporosis from the National Health and Nutrition Examination Survey from 2001 to 2018. Multivariate Cox regression models examined the correlation between serum 25(OH)D and all-cause mortality, cardiovascular mortality (CVD), and cancer mortality. The cohort included 9282 adult participants with a median follow-up period of 97.01 months, including 1394 all-cause deaths, 413 CVD-related deaths, and 322 cancer deaths. In fully adjusted models, higher serum 25(OH)D levels (≥75.0 nmol/L) were associated with a lower risk of all-cause mortality (hazard ratio 0.54, 95 % confidence interval 0.41 to 0.73) and cardiovascular death (0.47, 0.29 to 0.76), using participants with low 25(OH)D levels (<25 nmol/L) as the reference. In addition, we found an L-shaped non-linear dose-response relationship between serum 25(OH)D and all-cause and cardiovascular mortality, with inflection points of 38.8 nmol/L and 53.6 nmol/L, respectively.
Conclusion
Higher serum 25(OH)D concentrations are strongly associated with a diminished risk of all-cause and CVD mortality in patients with osteopenia or osteoporosis. This association has a threshold effect. More in-depth intervention studies are needed to clarify underlying mechanisms.
{"title":"Associations of the serum 25-hydroxyvitamin D with mortality among patients in osteopenia or osteoporosis","authors":"Ming Ma , Yuji Zhang , Jinmin Liu , Cong Tian , Zhenkun Duan , Xingchun Huang , Bin Geng","doi":"10.1016/j.bone.2025.117408","DOIUrl":"10.1016/j.bone.2025.117408","url":null,"abstract":"<div><h3>Purpose</h3><div>The correlation between serum 25-hydroxy vitamin D [(25(OH)D] and mortality in patients with osteopenia or osteoporosis remains unclear. Therefore, this study examined the relationship between serum 25(OH)D and mortality in patients with osteopenia or osteoporosis.</div></div><div><h3>Methods and results</h3><div>This prospective cohort study included patients with osteopenia or osteoporosis from the National Health and Nutrition Examination Survey from 2001 to 2018. Multivariate Cox regression models examined the correlation between serum 25(OH)D and all-cause mortality, cardiovascular mortality (CVD), and cancer mortality. The cohort included 9282 adult participants with a median follow-up period of 97.01 months, including 1394 all-cause deaths, 413 CVD-related deaths, and 322 cancer deaths. In fully adjusted models, higher serum 25(OH)D levels (≥75.0 nmol/L) were associated with a lower risk of all-cause mortality (hazard ratio 0.54, 95 % confidence interval 0.41 to 0.73) and cardiovascular death (0.47, 0.29 to 0.76), using participants with low 25(OH)D levels (<25 nmol/L) as the reference. In addition, we found an L-shaped non-linear dose-response relationship between serum 25(OH)D and all-cause and cardiovascular mortality, with inflection points of 38.8 nmol/L and 53.6 nmol/L, respectively.</div></div><div><h3>Conclusion</h3><div>Higher serum 25(OH)D concentrations are strongly associated with a diminished risk of all-cause and CVD mortality in patients with osteopenia or osteoporosis. This association has a threshold effect. More in-depth intervention studies are needed to clarify underlying mechanisms.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"193 ","pages":"Article 117408"},"PeriodicalIF":3.5,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-23DOI: 10.1016/j.bone.2025.117407
Pnina Rotman-Pikielny , Liat Barzilai-Yosef , Erez Ramaty , Sofia Braginski-Shapira , Michal Kasher Meron , Tzipi Hornik Lurie
The objective of this retrospective, database study was to characterize the rate, magnitude and timeline of increases in parathyroid hormone (PTH) levels post-denosumab (DMAb) vs. zoledronic acid (ZA) injection in patients with osteoporosis and near normal baseline PTH. Included were osteoporotic females, 50 years, initiating treatment with 60 mg DMAb or 5 mg ZA. PTH levels within 6-months post-DMAb or 12-months post-ZA injection were extracted from the electronic database of a 4.5 million-member health maintenance organization. The indication for PTH measurements was unknown. Exclusion criteria were creatinine >2 mg/dL, vitamin D < 50 nmol/L or parathyroid hormone level > 1.5 × upper limit of normal (ULN). Among 3317 women, 1992 received DMAb and 1325 ZA. The DMAb group was older (73.3 ± 8.5 vs. 69.8 ± 8.6 years, p < 0.001) and more patients treated with DMAb compared with patients treated with ZA had prior non-vertebral fractures (7.7 % vs. 5.2 %, p < 0.01) and had previously been treated with osteoporosis medication (56.3 % vs. 50.3 %, p < 0.001). Among the patients, 14.9 % had at least one post-treatment PTH > 1.5 ULN. Of 7273 post-treatment PTH tests, 62.6 % were within normal limits, while 24.8 % were mildly elevated at 1.01–1.5 ULN. Two-months after both treatments, >1.5 ULN PTH levels peaked at ∼20 %. Elevated PTH was associated with eGFR < 60 mL/min/1.73 m2 and comorbidities. In conclusion, most PTH levels post-DMAb or ZA in osteoporotic patients with baseline PTH < 1.5 ULN, were within normal range. PTH increased to >1.5 ULN in 14.9 % of patients; peaking in the first 2-months post-treatment and declining thereafter. Elevated PTH may be related to anti-resorptive effects and is not medication specific. PTH measurements in the first few months post-DMAb and ZA therapy should be limited.
{"title":"Parathyroid hormone levels following denosumab vs. zoledronic acid therapy for osteoporosis","authors":"Pnina Rotman-Pikielny , Liat Barzilai-Yosef , Erez Ramaty , Sofia Braginski-Shapira , Michal Kasher Meron , Tzipi Hornik Lurie","doi":"10.1016/j.bone.2025.117407","DOIUrl":"10.1016/j.bone.2025.117407","url":null,"abstract":"<div><div>The objective of this retrospective, database study was to characterize the rate, magnitude and timeline of increases in parathyroid hormone (PTH) levels post-denosumab (DMAb) vs. zoledronic acid (ZA) injection in patients with osteoporosis and near normal baseline PTH. Included were osteoporotic females, <span><math><mo>≥</mo></math></span>50 years, initiating treatment with 60 mg DMAb or 5 mg ZA. PTH levels within 6-months post-DMAb or 12-months post-ZA injection were extracted from the electronic database of a 4.5 million-member health maintenance organization. The indication for PTH measurements was unknown. Exclusion criteria were creatinine >2 mg/dL, vitamin D < 50 nmol/L or parathyroid hormone level > 1.5 × upper limit of normal (ULN). Among 3317 women, 1992 received DMAb and 1325 ZA. The DMAb group was older (73.3 ± 8.5 vs. 69.8 ± 8.6 years, <em>p</em> < 0.001) and more patients treated with DMAb compared with patients treated with ZA had prior non-vertebral fractures (7.7 % vs. 5.2 %, <em>p</em> < 0.01) and had previously been treated with osteoporosis medication (56.3 % vs. 50.3 %, <em>p</em> < 0.001). Among the patients, 14.9 % had at least one post-treatment PTH > 1.5 ULN. Of 7273 post-treatment PTH tests, 62.6 % were within normal limits, while 24.8 % were mildly elevated at 1.01–1.5 ULN. Two-months after both treatments, >1.5 ULN PTH levels peaked at ∼20 %. Elevated PTH was associated with eGFR < 60 mL/min/1.73 m<sup>2</sup> and comorbidities. In conclusion, most PTH levels post-DMAb or ZA in osteoporotic patients with baseline PTH < 1.5 ULN, were within normal range. PTH increased to >1.5 ULN in 14.9 % of patients; peaking in the first 2-months post-treatment and declining thereafter. Elevated PTH may be related to anti-resorptive effects and is not medication specific. PTH measurements in the first few months post-DMAb and ZA therapy should be limited.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"193 ","pages":"Article 117407"},"PeriodicalIF":3.5,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-23DOI: 10.1016/j.bone.2025.117404
Mathieu Simon , Silvia Owusu , Stefan Bracher , Dieter D. Bosshardt , Michael Pretterklieber , Philippe Zysset
Osteoporosis is the most common bone metabolic unbalance, leading to fragility fractures, which are known to be associated with structural changes in the bone. Cortical bone accounts for 80 % of the skeleton mass and undergoes remodeling throughout life, leading to changes in its thickness and microstructure. Although many studies quantified the different cortical bone structures using CT techniques (3D), they are often realised on a small number of samples. Therefore, the work presented here proposes a method to quantify cortical bone microstructure using 2D histology, shows its application on a set of 94 samples and compares to 3D methods.
Fresh frozen human femur pairs from 47 donors aged between 57 and 96 years were obtained from the Medical University of Vienna. Bone samples were cut from 3 sites: proximal part of the diaphysis, inferior and superior segments of the neck. The samples were stained with toluidine blue and imaged under light microscopy. After manual segmentation of a few regions of interest by multiple operators, a convolutional neural network was trained in combination with a random forest for automatic segmentation. The segmentation analysis compares morphology and structure distribution of Haversian canals, osteocyte lacunae, and cement lines with literature, between anatomical sites, sex, left and right sides, and relation to ageing.
Morphological analysis of the segmentation gives results similar to the literature. Comparison between male and female donors shows no significant differences. There is no significant difference between left and right femur on paired samples but significant differences are observed between anatomical locations. The structures' relative amounts do not present significant changes with age but only weak tendencies. Nevertheless, a strong correlation was observed between osteocyte lacunae density and bone areal fraction.
This study presents a full process to stain and automatically segment digital cortical bone images. Its application to a large sample set of proximal femora provides strong statistics on the cortical bone structures morphology and distribution. Similarities observed between sides and sexes together with differences observed between sites could indicate that mechanical loading might be a main driver for bone microstructure. Additionally, the relationship between osteocyte lacunae density and bone areal fraction could suggest that bone porosity is regulated by osteocyte survival.
{"title":"Automatic segmentation of cortical bone microstructure: Application and analysis of three proximal femur sites","authors":"Mathieu Simon , Silvia Owusu , Stefan Bracher , Dieter D. Bosshardt , Michael Pretterklieber , Philippe Zysset","doi":"10.1016/j.bone.2025.117404","DOIUrl":"10.1016/j.bone.2025.117404","url":null,"abstract":"<div><div>Osteoporosis is the most common bone metabolic unbalance, leading to fragility fractures, which are known to be associated with structural changes in the bone. Cortical bone accounts for 80 % of the skeleton mass and undergoes remodeling throughout life, leading to changes in its thickness and microstructure. Although many studies quantified the different cortical bone structures using CT techniques (3D), they are often realised on a small number of samples. Therefore, the work presented here proposes a method to quantify cortical bone microstructure using 2D histology, shows its application on a set of 94 samples and compares to 3D methods.</div><div>Fresh frozen human femur pairs from 47 donors aged between 57 and 96 years were obtained from the Medical University of Vienna. Bone samples were cut from 3 sites: proximal part of the diaphysis, inferior and superior segments of the neck. The samples were stained with toluidine blue and imaged under light microscopy. After manual segmentation of a few regions of interest by multiple operators, a convolutional neural network was trained in combination with a random forest for automatic segmentation. The segmentation analysis compares morphology and structure distribution of Haversian canals, osteocyte lacunae, and cement lines with literature, between anatomical sites, sex, left and right sides, and relation to ageing.</div><div>Morphological analysis of the segmentation gives results similar to the literature. Comparison between male and female donors shows no significant differences. There is no significant difference between left and right femur on paired samples but significant differences are observed between anatomical locations. The structures' relative amounts do not present significant changes with age but only weak tendencies. Nevertheless, a strong correlation was observed between osteocyte lacunae density and bone areal fraction.</div><div>This study presents a full process to stain and automatically segment digital cortical bone images. Its application to a large sample set of proximal femora provides strong statistics on the cortical bone structures morphology and distribution. Similarities observed between sides and sexes together with differences observed between sites could indicate that mechanical loading might be a main driver for bone microstructure. Additionally, the relationship between osteocyte lacunae density and bone areal fraction could suggest that bone porosity is regulated by osteocyte survival.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"193 ","pages":"Article 117404"},"PeriodicalIF":3.5,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143043960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-18DOI: 10.1016/j.bone.2025.117393
Mads Bloch-Ibenfeldt , Anne Theil Gates , Niklas Rye Jørgensen , Allan Linneberg , Mette Aadahl , Michael Kjær , Carl-Johan Boraxbekk
<div><h3>Objectives</h3><div>Maintained bone health is critical for independent living when aging. Currently, multimodal exercise regimes including weight-bearing exercises with impact are prescribed as optimal for maintaining bone health, while there is less consensus on the effects of resistance training at different intensities upon bone. Here we examined whether bone health was positively influenced by 1 year of supervised resistance training at two different intensities.</div></div><div><h3>Methods</h3><div>Older adults at retirement age (mean age: 66 ± 3 years, n = 451) were randomized to either 1 year of heavy resistance training (HRT), moderate intensity training (MIT) or a non-exercising control group (CON) in the LISA (LIve active Successful Aging) study. Bone mineral density (BMD) was assessed at whole body level, femoral neck, and the lumbar region of the spine (L1–L4) using Dual-energy X-ray absorptiometry (DXA). Bone degradation and formation were evaluated with blood C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-propeptide (PINP). Dephosphorylated uncarboxylated matrix Gla-protein (dp-ucMGP) was used as a biomarker of functional vitamin K status. Participants were assessed at baseline, immediately following the intervention (year 1), and at longitudinal follow-ups at years 2 and 4. Two-way mixed model ANOVAs were used to assess group differences at all time points.</div></div><div><h3>Results</h3><div>At the 4-year follow-up n = 329 participants (58 % women) remained in the study. BMD was not influenced by training and decreased across all groups over the 4 years for total body (F<sub>3,977</sub> = 4.617, p = 0.003, <span><math><msup><mi>η</mi><mn>2</mn></msup></math></span> = 0.01) and femoral neck both in the dominant (F<sub>3,893</sub> = 45.135, p < 0.001, <span><math><msup><mi>η</mi><mn>2</mn></msup></math></span> = 0.13) and non-dominant leg (F<sub>3,896</sub> = 33.821, p < 0.001, <span><math><msup><mi>η</mi><mn>2</mn></msup></math></span> = 0.10).</div><div>Independent of group, CTX increased (F<sub>3,932</sub> = 47.434, p < 0.001, <span><math><msup><mi>η</mi><mn>2</mn></msup></math></span> = 0.13) over the 4 years. HRT resulted in an increased bone formation (PINP rise) only after the first year with systematic training (t(936) = 3.357, p = 0.04), and it was more pronounced than in CON (t(312) = 2.494, p = 0.04). Plasma dp-ucMGP remained unaltered over time in all groups. In general, women had significantly lower BMD and higher levels of CTX and PINP compared to men.</div></div><div><h3>Conclusion</h3><div>We demonstrated that 1 year of heavy resistance training positively influenced short-term bone formation in well-functioning older adults, although the effect was not maintained at long-term follow ups. These minor changes in bone biomarkers were not reflected in changes in BMD measured with DXA.</div></div><div><h3>Trial registration</h3><div><span><span>clinicaltrials.gov</span><svg><p
{"title":"Heavy resistance training provides short-term benefits on bone formation in well-functioning older adults","authors":"Mads Bloch-Ibenfeldt , Anne Theil Gates , Niklas Rye Jørgensen , Allan Linneberg , Mette Aadahl , Michael Kjær , Carl-Johan Boraxbekk","doi":"10.1016/j.bone.2025.117393","DOIUrl":"10.1016/j.bone.2025.117393","url":null,"abstract":"<div><h3>Objectives</h3><div>Maintained bone health is critical for independent living when aging. Currently, multimodal exercise regimes including weight-bearing exercises with impact are prescribed as optimal for maintaining bone health, while there is less consensus on the effects of resistance training at different intensities upon bone. Here we examined whether bone health was positively influenced by 1 year of supervised resistance training at two different intensities.</div></div><div><h3>Methods</h3><div>Older adults at retirement age (mean age: 66 ± 3 years, n = 451) were randomized to either 1 year of heavy resistance training (HRT), moderate intensity training (MIT) or a non-exercising control group (CON) in the LISA (LIve active Successful Aging) study. Bone mineral density (BMD) was assessed at whole body level, femoral neck, and the lumbar region of the spine (L1–L4) using Dual-energy X-ray absorptiometry (DXA). Bone degradation and formation were evaluated with blood C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-propeptide (PINP). Dephosphorylated uncarboxylated matrix Gla-protein (dp-ucMGP) was used as a biomarker of functional vitamin K status. Participants were assessed at baseline, immediately following the intervention (year 1), and at longitudinal follow-ups at years 2 and 4. Two-way mixed model ANOVAs were used to assess group differences at all time points.</div></div><div><h3>Results</h3><div>At the 4-year follow-up n = 329 participants (58 % women) remained in the study. BMD was not influenced by training and decreased across all groups over the 4 years for total body (F<sub>3,977</sub> = 4.617, p = 0.003, <span><math><msup><mi>η</mi><mn>2</mn></msup></math></span> = 0.01) and femoral neck both in the dominant (F<sub>3,893</sub> = 45.135, p < 0.001, <span><math><msup><mi>η</mi><mn>2</mn></msup></math></span> = 0.13) and non-dominant leg (F<sub>3,896</sub> = 33.821, p < 0.001, <span><math><msup><mi>η</mi><mn>2</mn></msup></math></span> = 0.10).</div><div>Independent of group, CTX increased (F<sub>3,932</sub> = 47.434, p < 0.001, <span><math><msup><mi>η</mi><mn>2</mn></msup></math></span> = 0.13) over the 4 years. HRT resulted in an increased bone formation (PINP rise) only after the first year with systematic training (t(936) = 3.357, p = 0.04), and it was more pronounced than in CON (t(312) = 2.494, p = 0.04). Plasma dp-ucMGP remained unaltered over time in all groups. In general, women had significantly lower BMD and higher levels of CTX and PINP compared to men.</div></div><div><h3>Conclusion</h3><div>We demonstrated that 1 year of heavy resistance training positively influenced short-term bone formation in well-functioning older adults, although the effect was not maintained at long-term follow ups. These minor changes in bone biomarkers were not reflected in changes in BMD measured with DXA.</div></div><div><h3>Trial registration</h3><div><span><span>clinicaltrials.gov</span><svg><p","PeriodicalId":9301,"journal":{"name":"Bone","volume":"193 ","pages":"Article 117393"},"PeriodicalIF":3.5,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-18DOI: 10.1016/j.bone.2025.117401
Dianbin Liu , Yaoyao Xiang , Mengxin Sun , Jiayi Hu, Qiuchong Chen, Longxiang Liao, Yan Liu, Yanxia Wei
Porphyromonas gingivalis (P. gingivalis), a major pathogenic bacterium of chronic periodontitis and central player in the onset and subsequent progression of periodontitis, can cause alveolar bone resorption. The osteoblast dysfunction induced by P. gingivalis infection is a crucial pathological process causing bone loss. However, the comprehensive responses of osteoblasts, especially metabolism processes involved in osteoblast dysfunction under P. gingivalis invasion are largely unknown. In the present study, to profile the molecules switched in osteoblast dysfunction caused by P. gingivalis infection, the effect of P. gingivalis invasion on osteoblast differentiation was assessed and investigated through transcriptomics and metabolomics approaches. We found that P. gingivalis infection dramatically impaired osteoblast function. P. gingivalis invasion disrupted homeostasis of phosphorus (Pi)/calcium (Ca2+) and induced robust oxidative stress, cell apoptosis and massive activation of inflammatory response in osteoblasts. Notably, the exposure to P. gingivalis induced the inactivation of endocrines pathways, involved in bone formation, which is characterized by downregulated genes and less accumulated metabolites in “Parathyroid hormone synthesis, secretion and action”, its downstream “Wnt signaling pathway” and related Pi/Ca2+ transport. Furthermore, we found that disrupted purine metabolism produced less ATP in P. gingivalis-infected osteoblasts and the reduced ATP may directly inhibit phosphorus transport. Collectively, these results provide a new insight into the molecular changes in P. gingivalis-infected osteoblasts in a comprehensive way.
{"title":"Transcriptome and metabolome analysis of osteoblasts identifies disrupted purine metabolism and parathyroid hormone associated pathway induced by P. gingivalis infection","authors":"Dianbin Liu , Yaoyao Xiang , Mengxin Sun , Jiayi Hu, Qiuchong Chen, Longxiang Liao, Yan Liu, Yanxia Wei","doi":"10.1016/j.bone.2025.117401","DOIUrl":"10.1016/j.bone.2025.117401","url":null,"abstract":"<div><div><em>Porphyromonas gingivalis</em> (<em>P. gingivalis</em>), a major pathogenic bacterium of chronic periodontitis and central player in the onset and subsequent progression of periodontitis, can cause alveolar bone resorption. The osteoblast dysfunction induced by <em>P. gingivalis</em> infection is a crucial pathological process causing bone loss. However, the comprehensive responses of osteoblasts, especially metabolism processes involved in osteoblast dysfunction under <em>P. gingivalis</em> invasion are largely unknown. In the present study, to profile the molecules switched in osteoblast dysfunction caused by <em>P. gingivalis</em> infection, the effect of <em>P. gingivalis</em> invasion on osteoblast differentiation was assessed and investigated through transcriptomics and metabolomics approaches. We found that <em>P. gingivalis</em> infection dramatically impaired osteoblast function. <em>P. gingivalis</em> invasion disrupted homeostasis of phosphorus (Pi)/calcium (Ca<sup>2+</sup>) and induced robust oxidative stress, cell apoptosis and massive activation of inflammatory response in osteoblasts. Notably, the exposure to <em>P. gingivalis</em> induced the inactivation of endocrines pathways, involved in bone formation, which is characterized by downregulated genes and less accumulated metabolites in “Parathyroid hormone synthesis, secretion and action”, its downstream “Wnt signaling pathway” and related Pi/Ca<sup>2+</sup> transport. Furthermore, we found that disrupted purine metabolism produced less ATP in <em>P. gingivalis</em>-infected osteoblasts and the reduced ATP may directly inhibit phosphorus transport. Collectively, these results provide a new insight into the molecular changes in <em>P. gingivalis</em>-infected osteoblasts in a comprehensive way.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"193 ","pages":"Article 117401"},"PeriodicalIF":3.5,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Romosozumab is an anti-sclerostin antibody that increases bone formation and decreases bone resorption, and it became available for patients at high risk of osteoporotic fractures in Japan in 2019. The aim of this study was to clarify the clinical effects, safety, and predictors of the effectiveness of 12 months of romosozumab therapy following daily or weekly administration of teriparatide. The study had an observational pre–post design and included 171 female patients. Romosozumab was administered at a dose of 210 mg subcutaneously every 4 weeks for 12 months following daily or weekly administration of teriparatide. The incidence of new fractures, safety, and changes in bone mineral density (BMD) and bone turnover markers were recorded. New fractures occurred in 3 cases (2.2 %). Four patients (2.3 %) with secondary osteoporosis experienced cardiovascular events, which were fatal in 1 patient (0.6 %). The percent changes in BMD at the spine and total hip at 12 months from baseline were + 7.9 % and + 2.4 %, respectively. The percent change in spine BMD did not significantly differ according to whether daily or weekly teriparatide was given as previous treatment. Romosozumab following teriparatide showed greater effectiveness in patients with primary osteoporosis, high P1NP level at 1 month, and low percent changes in TRACP-5b after 12 months of treatment. Romosozumab after treatment with daily or weekly teriparatide was relatively safe and more effective in patients with primary osteoporosis than in those with secondary osteoporosis.
{"title":"Real-world safety and effectiveness of romosozumab following daily or weekly administration of teriparatide in primary and secondary osteoporosis","authors":"Kazuaki Mineta , Toshihiko Nishisho , Masahiko Okada , Mitsuhiro Kamada , Koichi Sairyo","doi":"10.1016/j.bone.2025.117392","DOIUrl":"10.1016/j.bone.2025.117392","url":null,"abstract":"<div><div>Romosozumab is an anti-sclerostin antibody that increases bone formation and decreases bone resorption, and it became available for patients at high risk of osteoporotic fractures in Japan in 2019. The aim of this study was to clarify the clinical effects, safety, and predictors of the effectiveness of 12 months of romosozumab therapy following daily or weekly administration of teriparatide. The study had an observational pre–post design and included 171 female patients. Romosozumab was administered at a dose of 210 mg subcutaneously every 4 weeks for 12 months following daily or weekly administration of teriparatide. The incidence of new fractures, safety, and changes in bone mineral density (BMD) and bone turnover markers were recorded. New fractures occurred in 3 cases (2.2 %). Four patients (2.3 %) with secondary osteoporosis experienced cardiovascular events, which were fatal in 1 patient (0.6 %). The percent changes in BMD at the spine and total hip at 12 months from baseline were + 7.9 % and + 2.4 %, respectively. The percent change in spine BMD did not significantly differ according to whether daily or weekly teriparatide was given as previous treatment. Romosozumab following teriparatide showed greater effectiveness in patients with primary osteoporosis, high P1NP level at 1 month, and low percent changes in TRACP-5b after 12 months of treatment. Romosozumab after treatment with daily or weekly teriparatide was relatively safe and more effective in patients with primary osteoporosis than in those with secondary osteoporosis.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"193 ","pages":"Article 117392"},"PeriodicalIF":3.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-13DOI: 10.1016/j.bone.2025.117391
Maja Østergaard, Nina Kølln Wittig, Henrik Birkedal
Accurate 3D characterization of osteocyte lacunae is important when investigating the role of osteocytes under various physiological and pathological conditions but remains a challenge. With the continued development of laboratory X-ray micro-computed tomography, an increasing number of studies employ these techniques beyond traditional bone morphometry to quantify osteocyte lacunae. However, there is a lack of knowledge on the effect of measurement parameters on the image quality and resolution and in turn the osteocyte lacunar quantification. Herein, we have examined the interplay between scan parameters and the resultant lacunar quantification in terms of lacunar size, shape, and density by comparison with a synchrotron benchmark dataset. We summarize our conclusions in a guide for use of μ-CT for osteocyte lacunar quantification: (1) Identification of the measurement requirements to address the research questions. (2) Collection and preparation of suitable sample(s) that fulfills these requirements. (3) Experimental considerations including determination of the required voxel size, in turn dictating the maximum FOV and by extension the maximum size of the sample(s). The experimental parameters chosen should ensure optimal image contrast, sufficient signal to noise, angular sampling etc. Usually, it is advisable to measure as well as possible within the limits of time, budget, data storage and analysis capabilities. (4) Data analysis and reporting of the results, including visual examination of the data at multiple steps in the analysis, to ensure correct feature identification and suitable reporting approaches. (5) Cross study comparisons, which may be unsuitable if the experimental conditions and analysis strategies are not comparable.
{"title":"A systematic study of the effect of measurement parameters on determination of osteocyte lacunar properties using laboratory X-ray micro-computed tomography","authors":"Maja Østergaard, Nina Kølln Wittig, Henrik Birkedal","doi":"10.1016/j.bone.2025.117391","DOIUrl":"10.1016/j.bone.2025.117391","url":null,"abstract":"<div><div>Accurate 3D characterization of osteocyte lacunae is important when investigating the role of osteocytes under various physiological and pathological conditions but remains a challenge. With the continued development of laboratory X-ray micro-computed tomography, an increasing number of studies employ these techniques beyond traditional bone morphometry to quantify osteocyte lacunae. However, there is a lack of knowledge on the effect of measurement parameters on the image quality and resolution and in turn the osteocyte lacunar quantification. Herein, we have examined the interplay between scan parameters and the resultant lacunar quantification in terms of lacunar size, shape, and density by comparison with a synchrotron <em>benchmark</em> dataset. We summarize our conclusions in a guide for use of μ-CT for osteocyte lacunar quantification: (1) Identification of the measurement requirements to address the research questions. (2) Collection and preparation of suitable sample(s) that fulfills these requirements. (3) Experimental considerations including determination of the required voxel size, in turn dictating the maximum FOV and by extension the maximum size of the sample(s). The experimental parameters chosen should ensure optimal image contrast, sufficient signal to noise, angular sampling etc. Usually, it is advisable to measure as well as possible within the limits of time, budget, data storage and analysis capabilities. (4) Data analysis and reporting of the results, including visual examination of the data at multiple steps in the analysis, to ensure correct feature identification and suitable reporting approaches. (5) Cross study comparisons, which may be unsuitable if the experimental conditions and analysis strategies are not comparable.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"193 ","pages":"Article 117391"},"PeriodicalIF":3.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143017339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-13DOI: 10.1016/j.bone.2025.117390
Irving M. Shapiro , Makarand V. Risbud , Tengteng Tang , William J. Landis
This paper presents a review of the potential role of the endoplasmic reticulum/Golgi complex and intracellular vesicles in mediating events leading to or associated with vertebrate tissue mineralization. The possible importance of these organelles in this process is suggested by observations that calcium ions accumulate in the tubules and lacunae of the endoplasmic reticulum and Golgi. Similar levels of calcium ions (approaching millimolar) are present in vesicles derived from endosomes, lysosomes and autophagosomes. The cellular level of phosphate ions in these organelles is also high (millimolar). While the source of these ions for mineral formation has not been identified, there are sound reasons for considering that they may be liberated from mitochondria during the utilization of ATP for anabolic purposes, perhaps linked to matrix synthesis. Published studies indicate that calcium and phosphate ions or their clusters contained as cargo within the intracellular organelles noted above lead to formation of extracellular mineral. The mineral sequestered in mitochondria has been documented as an amorphous calcium phosphate. The ion-, ion cluster- or mineral-containing vesicles exit the cell in plasma membrane blebs, secretory lysosomes or possibly intraluminal vesicles. Such a cell-regulated process provides a means for the rapid transport of ions or mineral particles to the mineralization front of skeletal and dental tissues. Within the extracellular matrix, the ions or mineral may associate to form larger aggregates and potential mineral nuclei, and they may bind to collagen and other proteins. How cells of hard tissues perform their housekeeping and other biosynthetic functions while transporting the very large volumes of ions required for mineralization of the extracellular matrix is far from clear. Addressing this and related questions raised in this review suggests guidelines for further investigations of the intracellular processes promoting the mineralization of the skeletal and dental tissues.
{"title":"Skeletal and dental tissue mineralization: The potential role of the endoplasmic reticulum/Golgi complex and the endolysosomal and autophagic transport systems","authors":"Irving M. Shapiro , Makarand V. Risbud , Tengteng Tang , William J. Landis","doi":"10.1016/j.bone.2025.117390","DOIUrl":"10.1016/j.bone.2025.117390","url":null,"abstract":"<div><div>This paper presents a review of the potential role of the endoplasmic reticulum/Golgi complex and intracellular vesicles in mediating events leading to or associated with vertebrate tissue mineralization. The possible importance of these organelles in this process is suggested by observations that calcium ions accumulate in the tubules and lacunae of the endoplasmic reticulum and Golgi. Similar levels of calcium ions (approaching millimolar) are present in vesicles derived from endosomes, lysosomes and autophagosomes. The cellular level of phosphate ions in these organelles is also high (millimolar). While the source of these ions for mineral formation has not been identified, there are sound reasons for considering that they may be liberated from mitochondria during the utilization of ATP for anabolic purposes, perhaps linked to matrix synthesis. Published studies indicate that calcium and phosphate ions or their clusters contained as cargo within the intracellular organelles noted above lead to formation of extracellular mineral. The mineral sequestered in mitochondria has been documented as an amorphous calcium phosphate. The ion-, ion cluster- or mineral-containing vesicles exit the cell in plasma membrane blebs, secretory lysosomes or possibly intraluminal vesicles. Such a cell-regulated process provides a means for the rapid transport of ions or mineral particles to the mineralization front of skeletal and dental tissues. Within the extracellular matrix, the ions or mineral may associate to form larger aggregates and potential mineral nuclei, and they may bind to collagen and other proteins. How cells of hard tissues perform their housekeeping and other biosynthetic functions while transporting the very large volumes of ions required for mineralization of the extracellular matrix is far from clear. Addressing this and related questions raised in this review suggests guidelines for further investigations of the intracellular processes promoting the mineralization of the skeletal and dental tissues.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"193 ","pages":"Article 117390"},"PeriodicalIF":3.5,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143018293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To evaluate the impact of prior teriparatide (TPTD) treatment on the effectiveness of romosozumab (ROMO) in postmenopausal osteoporosis.
Methods
In this retrospective, case-controlled, multicenter study, 323 postmenopausal patients were initiated ROMO. Of these, 275 were treatment-naïve, and 48 were switched from TPTD, with uninterrupted ROMO treatment for 12 months. Propensity score matching was applied to ensure clinical comparability, yielding 44 patients in each group. Baseline characteristics included a mean age of 78.0 years, lumbar spine (LS) T-score of −3.6, and total hip (TH) T-score of −2.8. Bone mineral density (BMD) and serum bone turnover markers were evaluated over the 12-month period.
Results
The increasing rate in the bone formation marker PINP was significantly greater in the treatment-naïve group compared to the TPTD-switched group throughout the 1–12 month period. Conversely, the reduction in the bone resorption marker TRACP-5b was similar between the groups, indicating a diminished anabolic window in the TPTD-switched group. After 12 months, the TPTD-switched group showed lower BMD gains in the LS (10.3 % vs. 17.3 %; P = 0.002) and TH (3.1 % vs. 7.8 %; P = 0.002) compared to the treatment-naïve group. Multiple regression analysis revealed positive associations between the 12-month percentage BMD increases (LS; β = 0.30; 95 % CI = 0.85–11.61; P = 0.024 / TH; β = 0.32; 95 % CI = 0.51–8.56; P = 0.028) and being treatment-naïve compared to prior TPTD treatment.
Conclusions
Prior TPTD treatment may attenuate the effectiveness of ROMO, potentially due to diminished bone formation activation.
{"title":"Impact of prior teriparatide treatment on the effectiveness of romosozumab in patients with postmenopausal osteoporosis: A case-control study","authors":"Kosuke Ebina , Tomonori Kobayakawa , Yuki Etani , Takaaki Noguchi , Masafumi Kashii , Gensuke Okamura , Yoshio Nagayama , Hideki Tsuboi , Akira Miyama , Makoto Hirao , Yuji Fukuda , Takuya Kurihara , Atsushi Sugimoto , Ken Nakata , Seiji Okada","doi":"10.1016/j.bone.2025.117389","DOIUrl":"10.1016/j.bone.2025.117389","url":null,"abstract":"<div><h3>Purpose</h3><div>To evaluate the impact of prior teriparatide (TPTD) treatment on the effectiveness of romosozumab (ROMO) in postmenopausal osteoporosis.</div></div><div><h3>Methods</h3><div>In this retrospective, case-controlled, multicenter study, 323 postmenopausal patients were initiated ROMO. Of these, 275 were treatment-naïve, and 48 were switched from TPTD, with uninterrupted ROMO treatment for 12 months. Propensity score matching was applied to ensure clinical comparability, yielding 44 patients in each group. Baseline characteristics included a mean age of 78.0 years, lumbar spine (LS) T-score of −3.6, and total hip (TH) T-score of −2.8. Bone mineral density (BMD) and serum bone turnover markers were evaluated over the 12-month period.</div></div><div><h3>Results</h3><div>The increasing rate in the bone formation marker PINP was significantly greater in the treatment-naïve group compared to the TPTD-switched group throughout the 1–12 month period. Conversely, the reduction in the bone resorption marker TRACP-5b was similar between the groups, indicating a diminished anabolic window in the TPTD-switched group. After 12 months, the TPTD-switched group showed lower BMD gains in the LS (10.3 % vs. 17.3 %; <em>P</em> = 0.002) and TH (3.1 % vs. 7.8 %; P = 0.002) compared to the treatment-naïve group. Multiple regression analysis revealed positive associations between the 12-month percentage BMD increases (LS; β = 0.30; 95 % CI = 0.85–11.61; <em>P</em> = 0.024 / TH; β = 0.32; 95 % CI = 0.51–8.56; <em>P</em> = 0.028) and being treatment-naïve compared to prior TPTD treatment.</div></div><div><h3>Conclusions</h3><div>Prior TPTD treatment may attenuate the effectiveness of ROMO, potentially due to diminished bone formation activation.</div></div>","PeriodicalId":9301,"journal":{"name":"Bone","volume":"193 ","pages":"Article 117389"},"PeriodicalIF":3.5,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}