bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-Detector Row CT Imaging of Vertebral Microstructure for Evaluation of Fracture Risk
Authors: Ito Masako , Ikeda Kyoji , Nishiguchi Masahiko , Shindo Hiroyuki , Uetani Masataka , Hosoi Takayuki , Orimo Hajime 
Published: April 2006

Abstract
We applied MDCT for in vivo evaluation of the microarchitecture of human vertebrae. Microstructure parameters, such as structure model index, Euler's number, and bone volume fraction, revealed higher relative risk for prevalent vertebral fracture than did BMD obtained by DXA. Thus, microstructure analysis by MDCT, together with simultaneously obtained volumetric BMD values, is useful for clinical assessment of fracture risk.
Introduction: BMD measurement by DXA alone has limitations in predicting fracture, and methods for clinical assessment of bone quality, such as microstructure, are awaited. This study was undertaken to examine the applicability of multidetector row CT (MDCT) for in vivo evaluation of trabecular microstructure.
Materials and Methods: Optimal conditions for MDCT scanning were determined at a spatial resolution of 250 × 250 × 500 μm, using μCT data of excised human vertebra specimens as a reference. We analyzed the trabecular microstructure of the vertebrae of 82 postmenopausal women (55-76 years old), including 39 women with and 43 without a recent vertebral fracture.
Results: Microstructure indices obtained by MDCT scanning revealed higher relative risk for prevalent vertebral fracture (OR: 16.0 for structure model index, 13.6 for bone volume fraction, and 13.1 for Euler's number) than did spinal BMD obtained by DXA (OR: 4.8). MDCT could also provide volumetric BMD data, which had higher diagnostic value (OR: 12.7) than did DXA.
Conclusion: Vertebral microarchitecture can be visualized by MDCT, and microstructure parameters obtained by MDCT, together with volumetric BMD, provided better diagnostic performance for assessing fracture risk than DXA measurement.
Effect of Long-Term Growth Hormone Treatment on Bone Mass and Bone Metabolism in Growth Hormone-Deficient Men
Authors: Bravenboer Nathalie , Holzmann Paulien J , ter Maaten Jan C , Stuurman Lotte M , Roos Jan C , Lips Paul 
Published: April 2006

Abstract
Long-term GH treatment in GH-deficient men resulted in a continuous increase in bone turnover as shown by histomorphometry. BMD continuously increased in all regions of interest, but more in the regions with predominantly cortical bone.
Introduction: Adults with growth hormone (GH) deficiency have reduced rates of bone turnover and subnormal BMD. GH treatment is effective in enhancing bone turnover as shown by biochemical markers and bone histomorphometric studies. However, it is uncertain whether long-term treatment will result in higher bone mass. In this study, we present BMD and histomorphometric data on 5 years of GH treatment in GH-deficient men.
Materials and Methods: Thirty-eight adult men with childhood onset GH deficiency (20-35 years) were included in the study. Twenty-six of these had multiple pituitary hormone deficiencies and were on stable conventional hormone replacement. BMC (total body) and BMD (lumbar spine and hip) were measured before and after 1, 2, 3, 4, and 5 years of treatment. BMD in various regions of the total body was calculated by computer software (head, trunk, arms, and legs). Transiliac bone biopsies were obtained before and after 1 and 5 years of GH treatment.
Results: Total body BMC increased 18% after 5 years of treatment. This increase was observed in all regions of interest: head, 13.7%; trunk, 27.8%; arms, 24.4%; legs, 13.8%. BMD also increased in all separately measured regions: lumbar spine, 9%; femoral neck, 11%; femoral trochanter, 16%. Lumbar spine area significantly increased (p = 0.0002). Histomorphometric data showed increased osteoid surface (p &lt; 0.02), osteoid volume (p &lt; 0.01), and activation frequency (p &lt; 0.006), but trabecular bone volume did not increase significantly. Qualitative assessment of the cortical bone showed endosteal and periosteal bone formation.
Conclusions: In conclusion, GH considerably increases BMC after long-term treatment. The combination of BMD and histomorphometric data suggests that GH has a greater effect on cortical than on trabecular bone.
Application of Histomorphometric Methods to the Study of Bone Repair
Authors: Gerstenfeld Louis C , Wronski Thomas J , Hollinger Jeffrey O , Einhorn Thomas A 
Published: April 2006

Abstract
ABSTRACT: Standardized methods for the histomorphometric assessment of bone are essential features of most studies of metabolic bone diseases and their treatments. These methodologies were developed to assess coupled remodeling, focusing primarily on osteoblasts and osteoclasts, the anabolic and catabolic rates of these cells, and structural features of mature bone. Research studies on bone healing and the development of new therapeutic approaches for the enhancement of bone repair also require a comprehensive understanding of the basic cellular and tissue level mechanisms that underlie these processes. However, the histological methods developed for metabolic bone disease studies are not completely suitable for studies of bone repair because they are based on assumptions that there is little variation in tissue composition within a sample of bone and not generally designed to quantify other types of tissues, such as cartilage, that contribute to bone healing. These techniques also do not provide tissue-based structural measurements that are relatable to the specific types of biomechanical and radiographic structural assessments that are used to determine rates of bone healing. These deficiencies in current histological approaches therefore point to the need to establish standardized criteria for the histomorphometric assessments that are specifically adapted for the study of bone repair in models of fracture healing and bone regeneration. In this Perspective, we outline what we believe to be the specific structural, tissue. and cellular aspects that need to be addressed to establish these standardized criteria for the histomorphometric assessment of bone repair. We present the specific technical considerations that need to be addressed to appropriately sample repair tissues to obtain statistically meaningful results and suggest specific procedures and definitions of nomenclatures for the application of this technology to bone repair. Finally, we present how aspects of histomorphometric measurements of bone repair can be related to biomechanical and radiographic imaging properties that functionally define rates of bone healing, and thus, how these tools can be used to provide corroborating data.
Rate of Forearm Bone Loss Is Associated With an Increased Risk of Fracture Independently of Bone Mass in Postmenopausal Women: The OFELY Study
Authors: Sornay-Rendu Elisabeth , Munoz Françoise , Duboeuf François , Delmas Pierre D 
Published: April 2006

Abstract
BMD is a major determinant of the risk of fragility fractures, but the role of the rate of postmenopausal bone loss is still unclear. In 671 postmenopausal women from the OFELY cohort, we found that the rate of bone loss was significantly associated with fracture risk independently of other well-known predictors including BMD and previous fractures.
Introduction: The level of BMD is a major determinant of the risk of fragility fractures, but the role of the rate of postmenopausal bone loss is still unclear.
Materials and Methods: In the OFELY study, we analyzed the risk of fracture in 671 postmenopausal women (mean age, 62.2 ± 9 years), according to the rate of bone loss. BMD was measured annually by DXA at the forearm, with a mean number of measurements of 10.3 ± 2.6. Peripheral fractures, all confirmed by radiographs, were prospectively registered, and vertebral fractures were evaluated with spine radiographs every 4 years.
Results: During a median (interquartile range [IQ]) of 11.2 years (11–12.3 years) of follow-up, 183 incident fragility fractures including 53 vertebral and 130 nonvertebral fractures were recorded in 134 women. The annual median ± IQ rate of bone loss, calculated from the slope, was −0.30 ± 0.76% at the mid-radius, −0.55 ± 0.79% at the distal radius, and −0.40 ± 0.96% at the ultradistal radius. Women with incident fracture had a rate of bone loss (before fracture) higher by 38–53% than those without fracture (p = 0.0003–0.016). Using multivariate Cox regression models, we found that bone loss in the highest tertile at the mid-radius, distal radius, and ultradistal radius was associated with a significant increased risk of all fractures with an hazard ratio from 1.45 to 1.70 (p = 0.02 to p = 0.009 after adjusting for age, previous fractures, maternal history of fracture, physical activity, grip strength, falls, and baseline BMD).
Conclusions: The rate of bone loss in postmenopausal women is significantly associated with fracture risk independently of other well-known predictors such as BMD and history of fractures.
Missense Mutations in LRP5 Are Not a Common Cause of Idiopathic Osteoporosis in Adult Men
Authors: Crabbe Patricia , Balemans Wendy , Willaert Andy , Van Pottelbergh Inge , Cleiren Erna , Coucke Paul J , Ai Minrong , Goemaere Stefan , Van Hul Wim , De Paepe Anne , Kaufman Jean-Marc 
Published: April 2006

Abstract
We studied whether the LRP5 gene contributes to the clinical phenotype of IO in men. Mutation analysis in 66 IO men revealed a range of sequence variants, of which two missense variants were shown to be of functional relevance.
Introduction: Mutations in the LDL receptor-related protein 5 (LRP5) gene have been associated with extreme bone phenotypes, which makes LRP5 a plausible candidate gene for idiopathic osteoporosis (IO).
Materials and Methods: In 66 men with IO, all 23 exons and exon-intron boundaries of the LRP5 gene were screened for mutations, and functional analyses were performed for those that were putatively involved in the phenotype.
Results: Mutation analysis in the IO probands revealed five missense mutations, of which 1067C&gt;T (S356L), 1364C&gt;T (S455L), and 4609G&gt;A (A1537T) were of potential functional significance because they were located in highly conserved regions of LRP5 and not found in a control panel. Segregation analysis in the respective families could not exclude their possible causality for IO. Furthermore, functional analyses clearly showed an inhibitory effect of mutations 1067C&gt;T and 1364C&gt;T on Wnt signal transduction. These effects are most likely caused by impaired LRP5 synthesis in the case of 1067C&gt;T and failure of protein trafficking to the cell surface for 1364C&gt;T.
Conclusions: For 2 of 66 IO probands, a mutation in the LRP5 gene with proven functionality was found. The findings indicate that carrying an LRP5 mutation is a risk factor for IO, but that overall, IO in men is infrequently underlied by such a mutation.
Self-Assembled RANK Induces Osteoclastogenesis Ligand-Independently
Authors: Kanazawa Kiyoshi , Kudo Akira 
Published: April 2006

Abstract
By immunoprecipitation assay, we showed that mouse RANK was self-assembled through its cytoplasmic domain located at position 534–539, whose domain was different form TRAF binding domains. Moreover, overexpression experiments showed that oligomeric RANK, which was self-associated, induced osteoclastogenesis ligand-independently.
Introduction: TNF receptor I or II (TNF-RI or TNF-RII) is thought to induce its own trimerization by ligand binding; however, recently TNF-RI or TNF-RII was shown to form a trimer through its extracellular domain without ligand binding. RANK, which plays an important role in osteoclast differentiation, is a member of the TNF receptor family. Here, we studied the self-assembly of mouse RANK.
Materials and Methods: Self-assembly of mouse RANK was examined by immunoprecipitation assay using 293T cells that had been transfected with the full-length RANK (Full) fused to FLAG tag (Full-FLAG) and Full fused to HA tag (Full-HA) without soluble RANKL (sRANKL). To explore the binding site for self-assembly, FLAG-tagged RANK C-terminal deletion mutants, 461-, 511-, 533-, 539-, and 544-FLAG, were constructed, and immunoprecipitation was performed. To examine whether RANK overexpression induced osteoclastogenesis, osteoclast progenitors that were derived from wildtype bone marrow cells, in which RANK was overexpressed, were cultured with monocyte-macrophage colony-stimulating factor (M-CSF), and TRACP staining was performed. We examined whether overexpression of each five individual C-terminal mutants induced osteoclastogenesis in osteoclast progenitors. To study the involvement of TRAF6 in RANK-induced osteoclastogenesis, osteoclast progenitors, in which RANK was overexpressed, were cultured with M-CSF and TNF receptor-associated factor (TRAF)6 decoy peptides (T6DP) that inhibit the interaction of RANK with TRAF6.
Results and Conclusions: Immunoprecipitation experiments showed that RANK was self-assembled without sRANKL. Among the five individual mutants, only 539- and 544-FLAG mutants were associated with Full-HA ligand-independently, suggesting that self-association of RANK was regulated by its cytoplasmic domain located at position 534–539. Overexpression of full-length RANK induced osteoclast differentiation, and this differentiation was suppressed by treatment with T6DP. Overexpression of RANK deletion mutants revealed that only 539- and 544-FLAG induced osteoclastogenesis. The five C-terminal mutants had the TRAF6 binding domain in their cytoplasmic regions, suggesting that ligand-independent osteoclastogenesis requires the receptor oligomerization of RANK.
Association of Amount of Physical Activity With Cortical Bone Size and Trabecular Volumetric BMD in Young Adult Men: The GOOD Study
Authors: Lorentzon Mattias , Mellström Dan , Ohlsson Claes 
Published: April 2006

Abstract
In this population-based study, amount of PA was associated with cortical bone size (increased thickness and periosteal circumference) and trabecular vBMD, but not with cortical vBMD or length of the long bones in young men. The lowest effective amount of PA was ≥4 h/week.
Introduction: Physical activity (PA) is believed to have positive effects on the skeleton and possibly help in preventing the occurrence of osteoporosis. Neither the lowest effective amount of PA needed to induce an osteogenic response nor its effect on the BMD and size of the different bone compartments (i.e., trabecular and cortical bone) has yet been clarified.
Materials and Methods: In this population-based study, we investigated the amount of all types of PA in relation to areal BMD (aBMD), trabecular and cortical volumetric BMD (vBMD), and cortical bone size in 1068 men (age, 18.9 ± 0.02 years), included in the Gothenburg Osteoporosis and Obesity Determinants (GOOD) study. aBMD was measured by DXA, whereas cortical and trabecular vBMD and bone size were measured by pQCT.
Results and Conclusions: The amount of PA was associated with aBMD of the total body, radius, femoral neck, and lumbar spine, as well as with cortical bone size (increased thickness and periosteal circumference) and trabecular vBMD, but not with cortical vBMD or length of the long bones. The lowest effective amount of PA was ≥4 h/week. aBMD, cortical bone size, and trabecular vBMD were higher in subjects who started their training before age 13 than in subjects who started their training later in life. Our data indicate that ≥4 h/week of PA is required to increase bone mass in young men and that exercise before and during the pubertal growth is of importance. These findings suggest that PA is imperative for the augmentation of cortical bone size and trabecular vBMD but does not affect the cortical vBMD in young men.
Novel Assessment of Bone Using Time-Resolved Transcutaneous Raman Spectroscopy
Authors: Draper Edward RC , Morris Michael D , Camacho Nancy P , Matousek Pavel , Towrie Mike , Parker Anthony W , Goodship Allen E 
Published: April 2006

Abstract
With fragility fractures increasing as the population ages, there is a need for improved means to estimate risk of fracture. We recorded Raman spectra of both the mineral and organic phases of bone transcutaneously, a technology with potential to enhance bone quality and fracture risk assessment.
Introduction: The current “gold standard” assessment of bone quality is BMD determined by DXA. However, this accounts for only 60–70% of bone strength. X-rays are absorbed by the mineral phase of bone, whereas the organic phase remains essentially invisible; however, bone strength is critically dependent on both phases. We report, for the first time, a Raman spectroscopic technique that analyses both phases of bone beneath unbroken skin by eliminating spectral components of overlying tissues.
Materials and Methods: We used an 800-nm laser (1-kHz, 1-ps pulses) with a synchronized 4-ps Kerr gate with variable picosecond delay that effectively shuttered out photons from overlying tissues. We measured bone Raman spectra at a point 2 mm above the carpus from two mouse genotypes with extreme differences in bone matrix quality: wildtype and oim/oim (matched for age, sex, and weight). Typical depth was 1.1 mm. We repeated the measurements with overlying tissues removed down to bone. Oim/oim mice produce only homotrimeric collagen, which results in poorly mineralized bone tissue.
Results: The main spectral features were present from both bone phases. The spectral bands were in similar ratios when measured through the skin or directly from bone (in both genotypes). The band of the mineral phase (phosphate ν1) was smaller in oim/oim mice when measured directly from bone and through skin. The band associated with a particular vibrational mode of organic phase collagen (CH2 wag) showed a frequency shift between the genotypes.
Conclusions: This novel technique allowed us, for the first time, to make objective transcutaneous spectral measurements of both the mineral and the organic phases of bones and distinguish between normal and unhealthy bone tissue. After further optimization, this technology may help improve fracture risk assessments and open opportunities for screening in anticipation of the predicted increase in fragility fractures.
Relationship Between Osteoporosis and Cardiovascular Disease in Postmenopausal Women
Authors: Tankó László B , Christiansen Claus , Cox David A , Geiger Mary Jane , McNabb Michelle A , Cummings Steven R 
Published: April 2006

Abstract
In the placebo group of the MORE study, including 2576 postmenopausal women (mean age, 66.5 years), the authors describe a strong linear association between the severity grade of osteoporosis (from low BMD to presence of severe vertebral fractures) and the future risk of cardiovascular events. Accordingly, treatment of postmenopausal osteoporosis should include consideration of measures to prevent adverse cardiovascular outcomes.
Introduction: Observations indicate an inverse association between BMD and the severity of peripheral atherosclerosis in postmenopausal women. The predictive value of osteoporosis and its different severity stages for the risk of acute cardiovascular events remains unknown.
Materials and Methods: Participants were 2576 women (mean age, 66.5 years) assigned to placebo and followed for 4 years in an osteoporosis treatment trial. Those with at least one vertebral fracture or total hip BMD T score ≤ −2.5 at baseline were defined as having osteoporosis, whereas those without vertebral fracture and total hip BMD T score between −2.5 and −1 were defined as having low bone mass. The primary outcome for these posthoc analyses was the incidence of adjudicated fatal or nonfatal cardiovascular events.
Results: After adjustment for potential confounders, women with osteoporosis had a 3.9-fold (95% CI, 2.0–7.7; p &lt; 0.001) increased risk for cardiovascular events compared with women with low bone mass. Under the same boundaries, a total hip BMD T score ≤ −2.5 versus a T score between −2.5 and −1 was associated with a 2.1-fold (95% CI, 1.2–3.6; p &lt; 0.01) increase in risk, whereas presence of at least one vertebral fracture versus no vertebral fracture at baseline was associated with a 3.0-fold (95% CI, 1.8–5.1; p &lt; 0.001) increase in risk. The risk of cardiovascular events increased incrementally with the number and increasing severity of baseline vertebral fractures (both p &lt; 0.001).
Conclusions: Postmenopausal women with osteoporosis are at an increased risk for cardiovascular events that is proportional to the severity of osteoporosis at the time of the diagnosis. Treatment of postmenopausal osteoporosis should include consideration of measures to prevent cardiovascular outcomes.
Skeletal Effects of Estrogen Are Mediated by Opposing Actions of Classical and Nonclassical Estrogen Receptor Pathways
Authors: Syed Farhan A , Mödder Ulrike IL , Fraser Daniel G , Spelsberg Thomas C , Rosen Clifford J , Krust Andree , Chambon Pierre , Jameson J Larry , Khosla Sundeep 
Published: April 2006

Abstract
ERα acts either through classical (ERE-mediated) or nonclassical (non-ERE) pathways. The generation of mice carrying a mutation that eliminates classical ERα signaling presents a unique opportunity to study the relative roles of these pathways in bone. This study defines the skeletal phenotype and responses to ovariectomy and estrogen replacement in these mice.
Introduction: Estrogen receptor α (ERα) can act either through classical estrogen response elements (EREs) or through non-ERE (nonclassical) pathways. To unravel these in bone, we crossed mice heterozygous for a knock-in mutation abolishing ERE binding (nonclassical ERα knock-in [NERKI]) with heterozygote ERα knockout mice and studied the resulting female ERα+/+, ERα+/NERKI, and ERα−/NERKI mice. The only ERα present in ERα−/NERKI mice is incapable of activating EREs but can signal through nonclassical pathways, whereas ERα+/NERKI mice may have a less drastic alteration in the balance between classical and nonclassical estrogen signaling pathways.
Materials and Methods: BMD was measured using DXA and pQCT at 3 months of age (n = 46–48/genotype). The mice were randomly assigned to sham surgery, ovariectomy, ovariectomy + estradiol (0.25 μg/day), or ovariectomy + estradiol (1.0 μg/day; n = 10–12/group) and restudied 60 days later.
Results and Conclusions: At 3 months of age, both the ERα+/NERKI and ERα−/NERKI mice had deficits in cortical, but not in trabecular, bone. Remarkably, changes in cortical bone after ovariectomy and estrogen replacement in ERα−/NERKI mice were the opposite of those in ERα+/+ mice. Relative to sham mice, ovariectomized ERα−/NERKI mice gained more bone (not less, as in ERα+/+ mice), and estrogen suppressed this increase (whereas augmenting it in ERα+/+ mice). Estrogen also had opposite effects on bone formation and resorption parameters on endocortical surfaces in ERα−/NERKI versus ERα+/+ mice. Collectively, these data show that alteration of the balance between classical and nonclassical ERα signaling pathways leads to deficits in cortical bone and also represent the first demonstration, in any tissue, that complete loss of classical ERE signaling can lead to paradoxical responses to estrogen. Our findings strongly support the hypothesis that there exists a balance between classical and nonclassical ERα signaling pathways, which, when altered, can result in a markedly aberrant response to estrogen.