bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polymorphisms in the Osteoprotegerin Gene Are Associated With Osteoporotic Fractures
Authors: Langdahl Bente L. , Carstens Mette , Stenkjaer Liselotte , Eriksen Erik Fink 
Published: April 2006

Abstract
Osteoprotegerin (OPG) is a soluble receptor for RANKL and therefore a competitive inhibitor of osteoclast differentiation and activity. With this key role in the control of resorptive activity, we found that OPG is a candidate gene for genetic control of bone mass. We examined the promoter and the five exons with surrounding intron sequences of the OPG gene for polymorphisms in 50 normal patients and 50 patients with osteoporosis. We found 12 polymorphisms. Two sets of four and five polymorphisms, respectively, were in complete linkage. Subsequently, we examined the effect of the informative polymorphisms A163-G (promoter), T245-G (promoter), T950-C (promoter), G1181-C (exon 1), and A6890-C (intron 4) on the prevalence of osteoporotic fractures, bone mass, and bone turnover in 268 osteoporotic patients and 327 normal controls. In A163-G the variant allele G was more common among fracture patients: 34.0% versus 26.3% in normal controls (p &lt; 0.05) and the odds ratio (OR) for a vertebral fracture, if an individual has the G allele, was 1.44 (1.00–2.08). In T245-G the variant allele G was more common in osteoporotic patients: 12.4% versus 6.5% (p &lt; 0.02) and the OR for vertebral fracture, if an individual has the G-allele, was 2.00 (1.10–3.62). G1181-C is located in the first exon and causes a shift in the third amino acid from lysine to asparagine. The CC genotype was less common among fracture patients: 26.3% versus 36.7% in the normal controls (p &lt; 0.01). T950-C and A6890-C were not distributed differently among patients with osteoporosis and normal controls. None of the polymorphisms affected bone mineral density (BMD) or biochemical markers of bone turnover in the normal controls. In conclusion, we have examined the human OPG gene for polymorphisms and found 12. The rare alleles of the A163-G and T245-G were significantly more common among patients with vertebral fractures.
A Short Pulse of Mechanical Force Induces Gene Expression and Growth in MC3T3-E1 Osteoblasts via an ERK 1/2 Pathway
Authors: Hatton Jason P , Pooran Milad , Li Chai-Fei , Luzzio Chris , Hughes-Fulford Millie 
Published: April 2006

Abstract
Physiological mechanical loading is crucial for maintenance of bone integrity and architecture. We have calculated the strain caused by gravity stress on osteoblasts and found that 4–30g corresponds to physiological levels of 40–300 μstrain. Short-term gravity loading (15 minutes) induced a 15-fold increase in expression of growth-related immediate early gene c-fos, a 5-fold increase in egr-1, and a 3-fold increase in autocrine bFGF. The non-growth-related genes EP-1, TGF-β, and 18s were unaffected by gravity loading. Short-term physiological loading induced extracellular signal-regulated kinase (ERK 1/2) phosphorylation in a dose-dependent manner with maximum phosphorylation saturating at mechanical loading levels of 12g (p &lt; 0.001) with no effect on total ERK. The phosphorylation of focal adhesion kinase (FAK) was unaffected by mechanical force. g-Loading did not activate P38 MAPK or c-jun N-terminal kinase (JNK). Additionally, a gravity pulse resulted in the localization of phosphorylated ERK 1/2 to the nucleus; this did not occur in unloaded cells. The induction of c-fos was inhibited 74% by the MEK1/2 inhibitor U0126 (p &lt; 0.001) but was not affected by MEK1 or p38 MAPK-specific inhibitors. The long-term consequence of a single 15-minute gravity pulse was a 64% increase in cell growth (p &lt; 0.001). U0126 significantly inhibited gravity-induced growth by 50% (p &lt; 0.001). These studies suggest that short periods of physiological mechanical stress induce immediate early gene expression and growth in MC3T3-E1 osteoblasts primarily through an ERK 1/2-mediated pathway.
Structural and Biomechanical Basis of Sexual Dimorphism in Femoral Neck Fragility Has Its Origins in Growth and Aging
Authors: Duan Yunbo , Beck Thomas J , Wang Xiao-Fang , Seeman Ego 
Published: April 2006

Abstract
The structural basis for sex differences in femoral neck (FN) fragility was studied in 1196 subjects and 307 patients with hip fracture. The absolute and relative patterns of modeling and remodeling on the periosteal and endocortical envelopes during growth and aging produce changes in FN geometry and structure that results in FN fragility in both sexes and sexual dimorphism in hip fracture risk in old age.
Introduction: Femoral neck (FN) fragility in old age is usually attributed to age-related bone loss, while the sex differences in hip fracture rate are attributed to less bone loss in men than in women. The purpose of this study was to define the structural and biomechanical basis underlying the increase in FN fragility in elderly men and women and the structural basis of sex differences in hip fracture incidence in old age.
Materials and Methods: We measured FN dimensions and areal bone mineral density in 1196 healthy subjects (801 females) 18–92 years of age and 307 patients (180 females) with hip fracture using DXA. We then used the DXA-derived FN areal bone mineral density (BMD) and measured periosteal diameter to estimate endocortical diameter, cortical thickness, section modulus (a measure of bending strength), and buckling ratio (indices for structural stability).
Results: Neither FN cortical thickness nor volumetric density differed in young adult women and men after height and weight adjustment. The sex differences in geometry were confined to the further displacement of the cortex from the FN neutral axis in young men, which produced 13.4% greater bending strength than in young women. Aging amplified this geometric difference; widening of the periosteal and endocortical diameters continued in both sexes but was greater in men, shifting the cortex even further from the neutral axis maintaining bending strength in men, not in women. In both sexes, less age-related periosteal than endocortical widening produced cortical thinning increasing the risk for structural failure by local buckling of the enlarged thin walled FN. Relative to age-matched controls, women and men with hip fractures had reduced cortical thickness, but FN periosteal diameter was increased in women and reduced in men, differences are likely to be originated in growth.
Conclusions: The absolute and relative patterns of modeling and remodeling on the periosteal and endocortical envelopes during growth and aging produce changes in FN diameters, cortical thickness, and geometry that results in FN fragility in both sexes and sexual dimorphism in hip fracture risk in old age.
BMD at Multiple Sites and Risk of Fracture of Multiple Types: Long-Term Results From the Study of Osteoporotic Fractures
Authors: Stone Katie L , Seeley Dana G , Lui Li-Yung , Cauley Jane A , Ensrud Kristine , Browner Warren S , Nevitt Michael C , Cummings Steven R 
Published: April 2006

Abstract
In a large cohort of U.S. women aged 65 and older, we report the relationships of BMD measured at several sites, and subsequent fracture risk at multiple sites over &gt;8 years of follow-up. Although we found almost all fracture types to be related to low BMD, the overall proportion of fractures attributable to low BMD is modest.
Introduction: Although several studies have reported the relationship between bone mineral density (BMD) and subsequent fracture risk, most have been limited by short follow-up time, BMD measures at only one or two sites, or availability of data for only select fracture types.
Materials and Methods: In the multicenter Study of Osteoporotic Fractures (SOF), we studied the relationship of several different BMD measures to fracture risk of multiple types in 9704 non-black women aged 65 and older. We previously reported on the relationship of peripheral BMD measures to risk of several types of fracture during an average 2.2-year follow-up period. In this expanded analysis, we present results of the relationship of both peripheral and central BMD measures and fractures of multiple types during 10.4 and 8.5 years of follow-up, respectively. We also report population attributable risk (PAR) estimates for osteoporosis and risk of several types of fracture.
Results: Our results show that almost all types of fractures have an increased incidence in women with low BMD. However, hip BMD is somewhat more strongly related to most of the fracture types studied than spine or peripheral BMD measures. Nonetheless, the proportion of fractures attributable to osteoporosis (based on a standard definition of osteoporosis) is modest, ranging from &lt;10% to 44% based on the most commonly used definition of osteoporosis (BMD T-score &lt; −2.5).
Conclusion: Finding effective prevention strategies for fractures in older women will require additional interventions beside preventions for bone loss, such as prevention of falls and other fracture risk factors.
Climbing Exercise Increases Bone Mass and Trabecular Bone Turnover Through Transient Regulation of Marrow Osteogenic and Osteoclastogenic Potentials in Mice
Authors: Mori Toshiharu , Okimoto Nobukazu , Sakai Akinori , Okazaki Yuichi , Nakura Nariaki , Notomi Takuya , Nakamura Toshitaka 
Published: April 2006

Abstract
To investigate the relationship between the effects of bone turnover and bone marrow cell development in bone cells, we developed a mouse voluntary climbing exercise model. Climbing exercise increased bone volume and transient osteogenic potential of bone marrow. This model would be suitable for investigating the mechanistic roles of mechanical loading.
Introduction: The relationship between bone mass gain and local bone formation and resorption in mechanically loaded bone is not well understood.
Materials and Methods: Sixty-five C57BL/6J mice, 8 weeks of age, were assigned to five groups: a baseline control and two groups each of ground control and climbing exercise mice for 2 and 4 weeks. Mice were housed in a 100-cm tower and had to climb toward a bottle placed at the top to drink water.
Results: Compared with the ground control, bone mineral density of the left femur increased in the climbing mice at 4 weeks. At 2 and 4 weeks, bone formation rate (BFR/BS) of periosteal surface, the cross-sectional area, and moment of inertia were increased in the climbing mice, whereas BFR/BS and eroded surface (ES/BS) of endosteal surface did not differ. The trabecular bone volume (BV/TV) of the proximal tibia increased in climbing mice, and osteoclast surface (Oc.S/BS) and osteoclast number decreased at 2 weeks. At 4 weeks, there were increases in BV/TV and parameters of bone formation, including mineralized surface, mineral apposition rate, and bone formation rate. In marrow cell cultures from the tibia, the number of alkaline phosphatase+ colony forming units-fibroblastic and the area of mineralized nodule formation in climbing mice were increased, and the number of osteoclast-like TRACP+ multinucleated cells was lower at 2 weeks. At 4 weeks, these parameters recovered to the levels of the ground controls.
Conclusion: Our results indicate that climbing increased trabecular bone volume and reduced bone resorption, with a subsequent increase in bone formation. Intermittent climbing downregulates marrow osteoclastogenic cells and upregulates osteogenic cells initially, but further exercise seemed to desensitize them. Cortical envelopes were enlarged earlier, but the response seems to differ from trabecular bone.
Zoledronic Acid Treatment Results in Retention of Femoral Head Structure After Traumatic Osteonecrosis in Young Wistar Rats
Authors: Little David G , Peat Rachel A , Mcevoy Anthony , Williams Paul R , Smith Elisabeth J , Baldock Paul A 
Published: April 2006

Abstract
Osteonecrosis (ON) of the femoral head in childhood can lead to loss of femoral head architecture and subsequent deformity. When femoral head ON was surgically induced in 24 rats, zoledronic acid treatment and prophylaxis improved sphericity and maintenance of architecture at 6 weeks. This preliminary experiment supports the use of bisphosphonates in childhood ON.
Introduction: We hypothesized that the bisphosphonate zoledronic acid could preserve femoral head structure while allowing bone repair.
Materials and Methods: Osteonecrosis (ON) was surgically induced in the right femoral head of 24 female Wistar rats. The rats were randomized into three treatment groups and dosed subcutaneously with saline, zoledronic acid (0.1 mg/kg) at 1 and 4 weeks postoperation (ZA post), or zoledronic acid (0.1 mg/kg) given 2 weeks preoperation and at 1 and 4 weeks postoperation (ZA pre-post). After death at 6 weeks postoperation, undecalcified specimens were analyzed by DXA and standardized histomorphometric analysis.
Results: Seventy-one percent of saline-operated femoral heads were aspherical (Mose score &gt; 1), whereas only 13% and 0% of operated heads in the ZA-treated groups were aspherical (p &lt; 0.05). DXA-measured bone mineral density in saline-treated femoral heads was reduced by 34% and 43% compared with the ZA-treated groups (p &lt; 0.01). Histomorphometry showed decreases of 12% and 17% in bone volume (BV/TV) in saline groups compared with ZA post and ZA pre-post (p &lt; 0.05), and a decrease in trabecular number (Tb.N) of 18% and 14% (p &lt; 0.05), respectively. Bone formation rate (BFR) was increased by 56% in saline-treated operated heads over ZA post and was 4.8 times increased over the ZA pre-post group (p &lt; 0.05). The differences in BV/TV and Tb.N in treated groups must therefore be caused by a reduction in bone turnover. Observational histology confirmed the retention of necrotic architecture in treated groups.
Conclusions: Zoledronic acid treatment and prophylaxis preserved femoral head architecture after traumatic ON in this rat model at 6 weeks. These data indicate that, by conserving femoral head architecture, bone repair may occur in conjunction with improved femoral head shape.
Rescue of the Pseudo-Vitamin D Deficiency Rickets Phenotype of CYP27B1-Deficient Mice by Treatment With 1,25-Dihydroxyvitamin D3: Biochemical, Histomorphometric, and Biomechanical Analyses
Authors: Dardenne Olivier , Prud'Homme José , Hacking S Adam , Glorieux Francis H , St-Arnaud René 
Published: April 2006

Abstract
The treatment of choice for pseudo-vitamin D deficiency rickets (PDDR), caused by mutations in the 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1; 1α-OHase) gene, is replacement therapy with 1,25(OH)2D3. We have previously engineered an animal model of PDDR by targeted inactivation of the 1α-OHase gene in mice. Replacement therapy was performed in this model. The 1α-OHase−/− mice and heterozygote controls were treated with 500 pg of 1,25(OH)2D3/g body weight/day for 2 weeks, followed by 100 pg of 1,25(OH)2D3/g body weight/day for an additional 3 weeks before death at 8 weeks of age. Blood biochemistry analysis revealed that the rescue treatment corrected the hypocalcemia and secondary hyperparathyroidism. The daily injections of 1,25(OH)2D3 induced strong expression of CYP24, the 25-hydroxyvitamin D 24-hydroxylase gene. Bone histology and histomorphometry confirmed that the rickets and osteomalacia were cured. The rescue regimen also restored the biomechanical properties of the bone tissue within normal parameters. These results show that chronic treatment with the active 1,25(OH)2D3 metabolite is effective to rescue the PDDR phenotype of 1α-OHase mutant mice.
Mechanical Loading Stimulates Dentin Matrix Protein 1 (DMP1) Expression in Osteocytes In Vivo
Authors: Gluhak-Heinrich Jelica , Ye Ling , Bonewald Lynda F , Feng Jian Q , MacDougall Mary , Harris Stephen E , Pavlin Dubravko 
Published: April 2006

Abstract
Dentin matrix protein 1 (DMP1) was originally postulated to be dentin specific. Further analysis showed that DMP1 is also expressed in mature cartilage and bone. In bone tissue, DMP1 is expressed predominantly in late osteoblasts and osteocytes. DMP1 belongs to the SIBLING (Small Integrin Binding Ligand N-linked Glycoprotein) family of cellular matrix proteins that also includes osteopontin, bone sialoprotein, dentin sialophosphoprotein, and others. In this study, we examined the effect of mechanical loading on expression of DMP1 mRNA and DMP1 protein in alveolar bone in the mouse tooth movement model by in situ hybridization and immunocytochemistry. The expression of DMP1 mRNA was determined quantitatively in mechanically loaded and control sites of dento-alveolar tissue at several time points from 6 h to 7 days after loading. The tooth movement model allows simultaneous evaluation of bone resorption and bone formation sites. Expression of DMP1 mRNA in osteocytes increased 2-fold as early as 6 h after treatment in both the bone formation and bone resorption sites. After 4 days, DMP1 expression in osteocytes increased to a maximum of 3.7-fold in the bone formation sites and 3.5-fold in the resorption sites. Osteoblasts responded in the opposite manner and showed a transient 45% decrease of DMP1 mRNA in bone formation sites and a constant decrease of DMP1 mRNA during the entire course of treatment in the bone resorption sites, with a peak inhibition of 67% at day 2. By immunocytochemistry using a C-terminal region peptide antibody to DMP1, we found that there was a transient decrease in immunoreactivity at 3 days after treatment on both the formation side and the resorption side compared with the matched contralateral control tissue. However by 7 days of loading, there was a dramatic increase in DMP1 protein immunoreactivity on both the formation side and the resorption side. These results represent changes in epitope availability using this antibody or true changes in protein levels. The observations imply that the DMP1 protein is undergoing dynamic changes in either synthesis or other protein/matrix interaction after mechanical loading of alveolar bone. The findings indicate that DMP1 is involved in the responses of osteocytes and osteoblasts to mechanical loading of bone. These results support the hypothesis that osteocytes alter their matrix microenvironment in response to mechanical loading.
Can Novel Clinical Densitometric Techniques Replace or Improve DXA in Predicting Bone Strength in Osteoporosis at the Hip and Other Skeletal Sites?
Authors: Lochmüller Eva-Maria , Müller Ralph , Kuhn Volker , Lill Christoph A , Eckstein Felix 
Published: April 2006

Abstract
New peripheral techniques are now available for the diagnosis of osteoporosis, but their value in the clinical management of the disease remains controversial. This study tests the hypothesis that peripheral quantitative computed tomography (pQCT) at the distal radius and/or quantitative ultrasound (QUS) at the calcaneus can serve as replacement or improvement of current methodology (QCT and DXA) for predicting bone strength at the hip and other sites. In 126 human cadavers (age, 80.2 ± 10.4 years), DXA of the femur, spine, and radius and pQCT of the radius were acquired with intact soft tissues. QCT (spine) and QUS (calcaneus) were performed ex situ in degassed specimens. Femoral failure loads were assessed in side impact and vertical loading. Failure loads of the thoracolumbar spine were determined at three levels in compression and those of the radius by simulating a fall. Site-specific DXA explained approximately 55% of the variability in femoral strength, whereas pQCT and QUS displayed a lower association (15-40%). QUS did not provide additional information on mechanical strength of the femur, spine, or radius. All techniques displayed similar capability in predicting a combined index of failure strength at these three sites, with only QUS exhibiting significantly lower associations than other methods. These experimental results suggest that clinical assessment of femoral fracture risk should preferably rely on femoral DXA, whereas DXA, QCT, and pQCT display similar capability of predicting a combined index of mechanical strength at the hip, spine, and radius.
Visual Identification of Vertebral Fractures in Osteoporosis Using Morphometric X-ray Absorptiometry
Authors: Ferrar L , Jiang G , Eastell R , Peel Nfa 
Published: April 2006

Abstract
Visual identification of vertebral fractures from spinal radiographs (visual XR) makes use of the reader's expertise in ruling out non-fracture deformities or normal variants. Scan images of the spine acquired by DXA may be analyzed quantitatively (morphometric X-ray absorptiometry [quantitative MXA]) or visually (visual MXA). The aims of this study were to compare visual and quantitative MXA with visual XR for the identification of vertebral fractures. Spinal radiographs and MXA scans were acquired at baseline and 1 year in 70 women referred with osteoporosis. These were assessed visually by two expert readers (observer A, a radiologist; observer B, a physician with expertise in osteoporosis) for evidence of prevalent and incident vertebral fractures. Observer C (a radiographer with expertise in vertebral morphometry) performed visual and quantitative assessments of the MXA scans. Visual assessment of spinal radiographs by observer A was used as the gold standard for comparison of methods. Sensitivity for the identification of prevalent fractures by MXA was best for visual MXA by observer A (92%), whereas quantitative MXA had the lowest sensitivity (82%). Specificity was &gt;90% for both visual and quantitative MXA. Kappa scores for agreement for identification of prevalent fractures between visual XR (observer A) and visual MXA (all three observers), and between visual XR and visual MXA performed by reader B were similar (κ = 0.85-0.87). Agreement with visual XR performed by observer A was slightly lower for quantitative MXA (κ = 0.77). Interobserver agreement between the two expert readers (observers A and B) was the same for both visual XR and visual MXA (κ = 0.86). Seven incident vertebral fractures were identified in four patients at follow-up. All four patients were identified by visual MXA, and three patients were identified by quantitative MXA. Observers A and B identified all seven incident fractures by visual MXA, and observer C missed one fracture that was also missed by quantitative MXA. An incident fracture of vertebra T6 was excluded from analysis by quantitative MXA because of poor image quality. We conclude that visual identification of vertebral fractures from MXA scans is superior to quantitative assessment. Used as a screening tool for conventional radiography, this approach could help reduce the radiation dose to the patient in the diagnosis and monitoring of osteoporosis.
Radioguided Parathyroidectomy for Recurrent Hyperparathyroidism Caused by Forearm Graft Hyperplasia
Authors: Sippel Rebecca S , Bianco Jesus , Chen Herbert 
Published: April 2006

Abstract
One of the surgical options for symptomatic secondary hyperparathyroidism is a total parathyroidectomy with forearm implantation. Recurrence can occur and is most likely caused by hyperplasia of the small fragments of parathyroid tissue implanted in the forearm muscle. Forearm graft hyperplasia can be detected using Tc-99m sestamibi scanning of the forearm, which can show abnormal enhancement at the former graft site. In this report, we present the case of a 49-year-old gentleman with recurrent hyperparathyroidism caused by hyperplasia of forearm graft fragments. Unfortunately, no sutures or clips were placed at his initial surgery to identify the location of the parathyroid tissue in the forearm. Thus, we describe the first reported use of radioguided techniques using Tc-99m sestamibi injection and intraoperative gamma probe to localize parathyroid fragments in the forearm muscle. During our initial exploration, we found that injection of the tracer in the operative arm leads to prohibitively high levels of background activity. During a second exploration, the tracer was injected in the lower extremity, minimizing the background in the forearm and allowing the gamma probe to clearly identify two areas of abnormal parathyroid tissue. The intraoperative radioprobe allowed quick identification and removal of the abnormal parathyroid tissue in a case that was made particularly challenging by the absence of marking sutures.