bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Improved Segmentation Method for In Vivo μCT Imaging
Authors: Waarsing Jan H , Day Judd S , Weinans Harrie 
Published: April 2006

Abstract
Image segmentation methods for μCT can influence the accuracy of bone morphometry calculations. A new automated segmentation method is introduced, and its performance is compared with standard segmentation methods. The new method can improve the results of in vivo μCT, where the need to keep radiation dose low limits scan quality.
Introduction: An important topic for μCT analysis of bone samples is the segmentation of the original reconstructed grayscale data sets to separate bone from non-bone. Problems like noise, resolution limitations, and beam-hardening make this a nontrivial issue. Inappropriate segmentation methods will reduce the potential power of μCT and may introduce bias in the architectural measurements, in particular, when new in vivo μCT with its inherent limitations in scan quality is used. Here we introduce a new segmentation method using local thresholds and compare its performance to standard global segmentation methods.
Material and Methods: The local threshold method was validated by comparing the result of the segmentation with histology. Furthermore, the effect of choosing this new method versus standard segmentation methods using global threshold values was investigated by studying the sensitivity of these methods to signal to noise ratio and resolution.
Results: Using the new method on high-quality scans yielded accurate results and virtually no differences between histology and the segmented data sets could be observed. When prior knowledge about the volume fraction of the bone was available the global threshold also resulted in appropriate results. Degrading the scan quality had only minor effects on the performance of the new segmentation method. Although global segmentation methods were not sensitive to noise, it was not possible to segment both lower mineralized thin trabeculae and the higher mineralized cortex correctly with the same threshold value.
Conclusion: At high resolutions, both the new local and conventional global segmentation methods gave near exact representations of the bone structure. When scanned samples are not homogenous (e.g., thick cortices and thin trabeculae) and when resolution is relatively low, the local segmentation method outperforms global methods. It maximizes the potential of in vivo μCT by giving good structural representation without the need to use longer scanning times that would increase absorption of harmful X-ray radiation by the living tissue.
Transient Retention of Endochondral Cartilaginous Matrix With Bisphosphonate Treatment in a Long-Term Rabbit Model of Distraction Osteogenesis
Authors: Smith Elisabeth J , McEvoy Anthony , Little David G , Baldock Paul A , Eisman John A , Gardiner Edith M 
Published: April 2006

Abstract
Bisphosphonates induce major increases in strength of callus in distraction osteogenesis in the short term. Poor understanding of the underlying mechanism, however, raises concerns about long-term consequences. In this long-term study in 32 rabbits, zoledronic acid transiently increased trabeculae by delayed temporal progression of endochondral bone remodeling but did not prevent radiographic completion of bone repair.
Introduction: We hypothesized that bisphosphonate inhibition of osteoclast-mediated resorption would retain bone during repair, producing a larger callus in the short term. However, if remodeling was not restored, completion of the bone repair process in the long term could be jeopardized.
Materials and Methods: Juvenile rabbits underwent right tibial osteotomy and 2 weeks of distraction, followed by a period of consolidation. Animals received saline (controls) or zoledronic acid (ZA; 0.1 mg/kg at surgery and again 2 weeks later), and distracted tibias were examined by radiograph, DXA, histology, and histomorphometry at 2, 4, 6, 18, and 44 weeks after surgery.
Results: Regenerated bone in ZA-treated animals was denser than controls on radiographs at 6 weeks and had more distinct radiodense trabeculae and retention of original cortices at 18 weeks. By 44 weeks, controls and ZA-treated animals were radiographically healed and indistinguishable. Regenerate BMD and BMC increased between 2 and 4 weeks in all animals, with a greater effect in ZA. At 6 weeks, BMD and BMC in ZA-treated animals were 1.6- and 2-fold greater, respectively, than controls (p &lt; 0.01). From 6 to 44 weeks, the control values gradually increased and approached the ZA-treated values. Regenerate bone volume and trabecular number by histomorphometry were from 1.6- to 2-fold greater in ZA-treated animals at 6 and 18 weeks (p &lt; 0.05). Endochondral cartilaginous matrix volume was up to 2.4-fold greater in ZA-treated animals at 2 and 4 weeks (p &lt; 0.05). TRACP+ cells in ZA-treated animals were larger with more nuclei. Mineral apposition rate and osteoblast number and surface were lower in ZA-treated animals at 6 weeks (p &lt; 0.01) but not at later times.
Conclusions: Disruption of TRACP+ cell function by ZA during bone regeneration seems to lead to an accretion of cancellous bone built on a larger endochondral cartilaginous matrix and increased bone mass, consistent with reported increases in short-term callus strength. This increase in bone mass, caused by a delay in remodeling, provided a transient advantage without preventing radiographic completion of the bone repair process in the long term. Noncontinuous treatment with nitrogen-containing bisphosphonates thus can have short-term beneficial effects without preventing long-term bone repair.
Bone Remodeling Increases Substantially in the Years After Menopause and Remains Increased in Older Osteoporosis Patients
Authors: Recker Robert , Lappe Joan , Davies K Michael , Heaney Robert 
Published: April 2006

Abstract
Bone remodeling rates (Ac.f) were measured in transilial biopsy specimens from 50 healthy premenopausal women before and 1 year after menopause, in 34 healthy women 13 years past menopause, and in 89 women with untreated osteoporosis. Ac.f nearly doubled 1 year after menopause, tripled 13 years after menopause, and remained elevated in women with osteoporosis.
Introduction: Increased bone remodeling rates are associated with increased skeletal fragility independent of bone mass, partially accounting for the age-related increase in fracture risk in women that is independent of bone loss. We examined bone remodeling rates before and after menopause and in women with osteoporosis by measurements of activation frequency (Ac.f, #/year) in transilial bone biopsy specimens.
Materials and Methods: We recruited 75 women, &gt;46 years old, who had premenopausal estradiol and gonadotropin levels and regular menses. During 9.5 years of observation, 50 women experienced normal menopause and had 2 transilial bone biopsy specimens after tetracycline labeling, one at the beginning of observation and the second 12 months after the last menses, when serum follicle-stimulating hormone (FSH) was &gt;75 mIU/ml and serum estradiol was &lt;20 pg/ml. Ac.f was also computed for a group of older healthy postmenopausal women and a group of women with untreated osteoporosis studied earlier by the same biopsy (Bx) and labeling protocol.
Results: Median Ac.f rose from 0.13/year to 0.24/year (p &lt; 0.001) across menopause and was greater still in the older normals (p &lt; 0.008) than in the second Bx. Ac.f was not significantly greater in the osteoporosis patients than in the older postmenopausal normals.
Conclusion: Bone remodeling rates double at menopause, triple 13 years later, and remain elevated in osteoporosis. This change contributes to increases in age-related skeletal fragility in women.
Malignant Autosomal Recessive Osteopetrosis Caused by Spontaneous Mutation of Murine Rank
Authors: Kapur Raj P , Yao Zhenqiang , Iida Malissa HK , Clarke Christine M , Doggett Barbara , Xing Lianping , Boyce Brendan F 
Published: April 2006

Abstract
We report the first case of lethal autosomal recessive osteopetrosis in mice caused by a spontaneous 8-bp deletion in exon 2 of the Rank gene. The phenotype, including a block in RANKL-dependent osteoclast differentiation and lymph node agenesis, copies that of Rank−/− mice, which have been produced by targeted recombination.
Introduction: Commitment of osteoclast progenitors to the osteoclast lineage requires RANKL/RANK-mediated intercellular signals. Gene-targeted defects in this signaling pathway resulted in osteoclast deficiency and severe osteopetrosis in mice, but to date, there have been no reports of spontaneous mutations in Rankl or Rank resulting in osteopetrosis.
Materials and Methods: Mice with malignant osteopetrosis and absent lymph nodes appeared spontaneously in a highly inbred colony. Appropriate crosses were analyzed to establish the pattern of inheritance. Tissues from affected pups and littermates were evaluated grossly, histopathologically, and radiographically. Osteoclast development from splenocytes was tested in vitro under a variety of conditions, including after infection with RANK-encoding retrovirus. Rank mutational analysis was performed by direct sequencing of RT-PCR products and genomic DNA.
Results: The inheritance pattern was consistent with autosomal recessive inheritance, and the phenotype resembled that of either Rankl or Rank knockout mice with the exception of as yet unexplained death of most mice 2–3 weeks after weaning. Osteoclast precursors from the spleens of affected pups failed to form osteoclasts in vitro when stimulated with macrophage-colony stimulating factor (M-CSF) and RANKL, unless they were forced to express wildtype Rank cDNA. Molecular genetic studies identified an 8-bp deletion in exon 2 of the Rank gene. The resulting allele, termed Rankdel8, encodes only a small portion of the RANK extracellular domain, which is probably nonfunctional.
Conclusions: The phenotypic similarities between Rankdel8 and mice previously described with a combined insertion and deletion in Rank confirm the role of this receptor in osteoclastogenesis and lymph node development and suggest that some forms of malignant osteopetrosis in humans could result from a similar defect.
Possible Roles of Runx1 and Sox9 in Incipient Intramembranous Ossification
Authors: Yamashiro Takashi , Wang Xiu-Ping , Li Zhe , Oya Shinji , Åberg Thomas , Fukunaga Tomohiro , Kamioka Hiroshi , Speck Nancy A , Takano-Yamamoto Teruko , Thesleff Irma 
Published: April 2006

Abstract
We evaluated the detailed expression patterns of Runx1 and Sox9 in various types of bone formation, and determined whether Runx1 expression was affected by Runx2 deficiency and Runx2 expression by Runx1 deficiency. Our results indicate that both Runx1 and Sox9 are intensely expressed in the future osteogenic cell compartment and in cartilage. The pattern of Runx1 and Sox9 expression suggests that both genes could potentially be involved in incipient intramembranous bone formation during craniofacial development.
Introduction: Runx1, a gene essential for hematopoiesis, contains RUNX binding sites in its promoter region, suggesting possible cross-regulation with Runx2 and potential regulatory roles in bone development. On the other hand, Sox9 is essential for chondrogenesis, and haploinsufficiency of Sox9 leads to premature ossification of the skeletal system. In this study, we studied the possible roles of Runx1 and Sox9 in bone development.
Materials and Methods: Runx1, Runx2/Osf2, and Sox9 expression was evaluated by in situ hybridization in the growing craniofacial bones of embryonic day (E)12–16 mice and in the endochondral bone-forming regions of embryonic and postnatal long bones. In addition, we evaluated Runx2/Osf2 expression in the growing face of Runx1 knockout mice at E12.5 and Runx1 expression in Runx2 knockout mice at E14.5.
Results: Runx1 and Sox9 were expressed in cartilage, and the regions of expression expanded to the neighboring Runx2-expressing osteogenic regions. Expression of both Runx1 and Sox9 was markedly downregulated on ossification. Runx1 and Sox9 expression was absent in the regions of endochondral bone formation and in actively modeling or remodeling bone tissues in the long bones as well as in ossified craniofacial bones. Runx2 expression was not affected by gene disruption of Runx1, whereas the expression domains of Runx1 were extended in Runx2−/− mice compared with wildtype mice.
Conclusions: Runx1 and Sox9 are specifically expressed in the osteogenic cell compartments in the craniofacial bones and the bone collar of long bones, and this expression is downregulated on terminal differentiation of osteoblasts. Our results suggest that Runx1 may play a role in incipient intramembranous bone formation.
Bone Fragility and Collagen Cross-Links
Authors: Paschalis Eleftherios P , Shane Elizabeth , Lyritis George , Skarantavos Grigoris , Mendelsohn Richard , Boskey Adele L 
Published: April 2006

Abstract
Infrared imaging analysis of iliac crest biopsy specimens from patients with osteoporotic and multiple spontaneous fractures shows significant differences in the spatial variation of the nonreducible:reducible collagen cross-links at bone-forming trabecular surfaces compared with normal bone.
Introduction: Although the role of BMC and bone mineral quality in determining fracture risk has been extensively studied, considerably less attention has been paid to the quality of collagen in fragile bone.
Materials and Methods: In this study, the technique of Fourier transform infrared imaging (FTIRI) was used to determine the ratio of nonreducible:reducible cross-links, in 2- to 4-μm-thick sections, from human iliac crest biopsy specimens (N = 27) at bone-forming trabecular surfaces. The biopsy specimens were obtained from patients that had been diagnosed as high- or low-turnover osteoporosis, as well as premenopausal women &lt;40 years of age, with normal BMD and biochemistry, who suffered multiple spontaneous fractures. The obtained values were compared with previously published analyses of trabecular bone from normal non-osteoporotic subjects (N = 14, 6 males and 8 females; age range, 51–70 years).
Results and Conclusions: Collagen cross-links distribution within the first 50 μm at forming trabecular surfaces in patients with fragile bone was markedly different compared with normal bone.
Epidemiology of Childhood Fractures in Britain: A Study Using the General Practice Research Database
Authors: Cooper Cyrus , Dennison Elaine M , Leufkens Herbert GM , Bishop Nicholas , van Staa Tjeerd P 
Published: April 2006

Abstract
A population-based British cohort study, including ∼6% of the population, was used to derive age- and sex-specific incidence rates of fractures during childhood. Fractures were more common among boys than girls, with peak incidences at 14 and 11 years of age, respectively. At childhood peak, incidence rates were only surpassed later in life at 85 years of age among women and never among men.
Introduction: Fractures account for 25% of accidents and injuries in childhood; however, the descriptive epidemiology of childhood fractures remains uncertain.
Materials and Methods: Age- and sex-specific incidence rates for fractures at various skeletal sites were derived from the General Practice Research Database (a population-based British cohort containing computerized medical records of ∼7,000,000 residents) between 1988 and 1998.
Results: A total of 52,624 boys and 31,505 girls sustained one or more fractures over the follow-up period, for a rate of 133.1/10,000 person-years. Fractures were more common in boys (161.6/10,000 person-years) than girls (102.9/10,000 person-years). The most common fracture in both sexes was that of the radius/ulna (30%). Fracture incidence was greater among boys than girls at all ages, with the peak incidence at 14 years of age among boys and 11 years of age among girls. Marked geographic variation was observed in standardized fracture incidence, with significantly (p &lt; 0.01) higher rates observed in Northern Ireland, Wales, and Scotland compared with southeast England.
Conclusions: Fractures are a common problem in childhood, with around one-third of boys and girls sustaining at least one fracture before 17 years of age. Rates are higher among boys than girls, and male incidence rates peak later than those among females. At their childhood peak, the incidence of fractures (boys, 3%; girls, 1.5%) is only surpassed at 85 years of age among women and never among men. The most common site affected in both genders is the radius/ulna. Studies to clarify the pathogenesis of these fractures, emphasizing bone fragility, are now required.
Primary Prevention of Osteoporosis: Mass Screening Scenario or Prescreening With Questionnaires? An Economic Perspective
Authors: Richy Florent , Ethgen Olivier , Bruyere Olivier , Mawet Audrey , Reginster Jean-Yves 
Published: April 2006

Abstract
This study focuses on the controversy surrounding selective approaches to screen for osteoporosis. Seven screening approaches were compared in terms of cost-effectiveness and incremental cost-effectiveness ratios in a sample of 4035 postmenopausal women. Our results show that certain prescreening strategies are more efficient than DXA-based approaches. These results are of considerable value for health policy decision-makers and the scientific community.
Introduction: There is no general consensus on the most efficient strategy to use bone densitometry for osteoporosis screening. Two distinct approaches have progressively emerged: mass screening using DXA and prescreening strategies using user-friendly risk indices. This study was designed to compare the efficiency of these approaches.
Materials and Methods: A database of 4035 medical records from postmenopausal women above 45 years was analyzed. In the first scenario, women were systematically referred to DXA if above 45, 50, or 65 years of age. The second scenario involved the validated prescreening tools SCORE, ORAI, OST, and OSIRIS and assessed two separate ways of handling their results (theoretical and pragmatic). The cost of a DXA test was set as the median Belgian value: 40.14£. All strategies were compared in terms of cost exposed per osteoporotic patient detected and in terms of incremental cost-effectiveness ratios.
Results: In the systematic DXA strategies, the cost per patient detected ranged from 123£ when measuring all women &gt;45 years of age to 91£ when focusing on women &gt;65 years of age. The corresponding percentage of cases detected ranged from 100% (age &gt; 45 years) to 50% (age &gt; 65 years). When considering prescreening under the theoretical and pragmatic scenarios, the OSIRIS index provided the best efficiency, with costs of 74£ (theoretical) to 85£ (pragmatic) per case detected, followed by ORAI (75£ and 96£), OST (84£ and 94£), and SCORE (96£ and 103£). The corresponding percentage of cases detected ranged from 89% (SCORE) to 75% (OSIRIS). The cost-effectiveness analysis showed that mass screening strategies over 50 and 65 years of age and using ORAI were best.
Conclusions: Our study sets the grounds for considering, in a health economics perspective, prescreening tools as valuable, cost-effective, approaches to significantly reduce the economic burden of osteoporosis screening.
Decreased BMD and Limb Deformities in Mice Carrying Mutations in Both Lrp5 and Lrp6
Authors: Holmen Sheri L , Giambernardi Troy A , Zylstra Cassandra R , Buckner-Berghuis Bree D , Resau James H , Hess J Fred , Glatt Vaida , Bouxsein Mary L , Ai Minrong , Warman Matthew L , Williams Bart O 
Published: April 2006

Abstract
Humans and mice lacking Lrp5 have low BMD. To evaluate whether Lrp5 and Lrp6 interact genetically to control bone or skeletal development, we created mice carrying mutations in both Lrp5 and the related gene Lrp6. We found that compound mutants had dose-dependent deficits in BMD and limb formation, suggesting functional redundancy between these two genes in bone and limb development.
Introduction: Lrp5 and Lrp6 are closely related members of the low density lipoprotein receptor family and are co-receptors for Wnt ligands. While Lrp5 mutations are associated with low BMD in humans and mice, the role of Lrp6 in bone formation has not been analyzed.
Materials and Methods: To address whether Lrp5 and Lrp6 play complimentary roles in bone and skeletal development, we created mice with mutations in both genes. We inspected limbs of mice from the different genotypic classes of compound mutants to identify abnormalities. DXA and μCT were used to evaluate the effect of mutations in Lrp5 and Lrp6 on BMD and microarchitecture.
Results: Mice heterozygous for mutations in Lrp6 and either heterozygous or homozygous for a mutation in Lrp5 (Lrp6+/−;Lrp5+/− or Lrp6+/−;Lrp5−/−) display limb defects with incomplete penetrance and variable expression. DXA analysis showed that BMD decreased as mice progressively were more deficient in Lrp5 and Lrp6. Lrp6+/−;Lrp5−/− mice were more severely affected than Lrp6+/+;Lrp5−/− mice, whereas Lrp6+/−;Lrp5+/− mice had statistically higher BMD than Lrp6+/+;Lrp5−/− mice and lower BMD compared with wildtype mice and mice heterozygous for either mutation alone.
Conclusions: Lrp6 and Lrp5 genetically interact in limb development in mice. Furthermore, heterozygosity for an inactivating mutation in Lrp6 further reduces BMD in both male and female mice lacking Lrp5.
Whole Body BMC in Pediatric Crohn Disease: Independent Effects of Altered Growth, Maturation, and Body Composition
Authors: Burnham Jon M , Shults Justine , Semeao Edisio , Foster Bethany , Zemel Babette S , Stallings Virginia A , Leonard Mary B 
Published: April 2006

Abstract
Whole body BMC was assessed in 104 children and young adults with CD and 233 healthy controls. CD was associated with significant deficits in BMC and lean mass, relative to height. Adjustment for lean mass eliminated the bone deficit in CD. Steroid exposure was associated with short stature but not bone deficits relative to height.
Introduction: Children with Crohn disease (CD) have multiple risk factors for impaired bone accrual. The confounding effects of poor growth and delayed maturation limit the interpretation of prior studies of bone health in CD. The objective of this study was to assess BMC relative to growth, body composition, and maturation in CD compared with controls.
Materials and Methods: Whole body BMC and lean mass were assessed by DXA in 104 CD subjects and 233 healthy controls, 4–26 years of age. Multivariable linear regression models were developed to sequentially adjust for differences in skeletal size, pubertal maturation, and muscle mass. BMC-for-height z scores were derived to determine CD-specific covariates associated with bone deficits.
Results: Subjects with CD had significantly lower height z score, body mass index z score, and lean mass relative to height compared with controls (all p &lt; 0.0001). After adjustment for group differences in age, height, and race, the ratio of BMC in CD relative to controls was significantly reduced in males (0.86; 95% CI, 0.83, 0.94) and females (0.91; 95% CI, 0.85, 0.98) with CD. Adjustment for pubertal maturation did not alter the estimate; however, addition of lean mass to the model eliminated the bone deficit. Steroid exposure was associated with short stature but not bone deficits.
Conclusion: This study shows the importance of considering differences in body size and composition when interpreting DXA data in children with chronic inflammatory conditions and shows an association between deficits in muscle mass and bone in pediatric CD.