bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monthly Oral Ibandronate Therapy in Postmenopausal Osteoporosis: 1-Year Results From the MOBILE Study
Authors: Miller Paul D , Mcclung Michael R , Macovei Liviu , Stakkestad Jacob A , Luckey Marjorie , Bonvoisin Bernard , Reginster Jean-Yves , Recker Robert R , Hughes Claire , Lewiecki E Michael , Felsenberg Dieter , Delmas Pierre D , Kendler David L , Bolognese Michael A , Mairon Nicole , Cooper Cyrus 
Published: April 2006

Abstract
Once-monthly (50/50, 100, and 150 mg) and daily (2.5 mg; 3-year vertebral fracture risk reduction: 52%) oral ibandronate regimens were compared in 1609 women with postmenopausal osteoporosis. At least equivalent efficacy and similar safety and tolerability were shown after 1 year.
Introduction: Suboptimal adherence to daily and weekly oral bisphosphonates can potentially compromise therapeutic outcomes in postmenopausal osteoporosis. Although yet to be prospectively shown in osteoporosis, evidence from randomized clinical trials in several other chronic conditions shows that reducing dosing frequency enhances therapeutic adherence. Ibandronate is a new and potent bisphosphonate with antifracture efficacy proven for daily administration and also intermittent administration with a dose-free interval of &gt;2 months. This report presents comparative data on the efficacy and safety of monthly and daily oral ibandronate regimens.
Materials and Methods: MOBILE is a 2-year, randomized, double-blind, phase III, noninferiority trial. A total of 1609 women with postmenopausal osteoporosis were assigned to one of four oral ibandronate regimens: 2.5 mg daily, 50 mg/50 mg monthly (single doses, consecutive days), 100 mg monthly, or 150 mg monthly.
Results: After 1 year, lumbar spine BMD increased by 3.9%, 4.3%, 4.1%, and 4.9% in the 2.5, 50 /50, 100, and 150 mg arms, respectively. All monthly regimens were proven noninferior, and the 150 mg regimen superior, to the daily regimen. All monthly regimens produced similar hip BMD gains, which were larger than those with the daily regimen. All regimens similarly decreased serum levels of C-telopeptide, a biochemical marker of bone resorption. Compared with the daily regimen, a significantly larger proportion of women receiving the 100 and 150 mg monthly regimens achieved predefined threshold levels for percent change from baseline in lumbar spine (6%) or total hip BMD (3%). All regimens were similarly well tolerated.
Conclusions: Monthly ibandronate is at least as effective and well tolerated as the currently approved daily ibandronate regimen in postmenopausal osteoporosis.
Asymptomatic Vertebral Deformity as a Major Risk Factor for Subsequent Fractures and Mortality: A Long‐Term Prospective Study
Authors: Pongchaiyakul Chatlert , Nguyen Nguyen D , Jones Graeme , Center Jacqueline R , Eisman John A , Nguyen Tuan V 
Published: April 2006

AbstractIn elderly men and women, asymptomatic vertebral deformity was found to be associated with subsequent risk of symptomatic fractures, particularly vertebral fracture, and increased risk of mortality after a fracture.Introduction: Vertebral deformity is associated with an increased risk of fracture and mortality. However, it is unclear whether the three events of vertebral deformity, fracture, and mortality are linked with each other and what role BMD plays in these linkages.Materials and Methods: Vertebral deformity was determined from quantitative analysis of thoracolumbar spine X‐rays in 300 randomly individuals (114 men and 186 women) ⩾60 years of age (as of mid‐1989), who were randomly selected from the prospective Dubbo Osteoporosis Epidemiology Study. Incidence of atraumatic fractures and subsequent mortality were ascertained from 1989 to 2003. Cox's proportional hazards model was used to determine the association between asymptomatic vertebral deformities, osteoporotic fractures, and risk of mortality.Results: The prevalence of asymptomatic vertebral deformity was 31% in men and 17% in women. During the follow‐up period, subjects with vertebral deformity had a significantly higher risk of any fracture than those without vertebral deformity (44% versus 29%; hazards ratio [HR], 2.2; 95% CI, 1.4‐3.7), particularly symptomatic vertebral fracture (relative risk [RR], 7.4; 95% CI, 3.2‐17.0). Mortality rate was highest after a symptomatic fracture among those with vertebral deformity (HR, 9.0; 95% CI, 3.1‐26.0). These associations were independent of age, sex, and BMD.Conclusion: Vertebral deformity was a strong predictor of subsequent risk of fractures, particularly symptomatic vertebral fracture, and may modify fracture‐associated mortality in both elderly men and women.
Type XIII Collagen Strongly Affects Bone Formation in Transgenic Mice
Authors: Ylönen Riikka , Kyrönlahti Tuomo , Sund Malin , Ilves Mika , Lehenkari Petri , Tuukkanen Juha , Pihlajaniemi Taina 
Published: April 2006

Abstract
To characterize the function of type XIII collagen, a transmembrane protein occurring at cell adhesion sites, we generated transgenic mice overexpressing it. High transgene expression was detected in cartilage and bone. The overexpression mice developed an unexpected skeletal phenotype marked by a massive increase in bone mass caused by increased bone formation rather than impaired resorption.
Introduction: Type XIII collagen is a type II transmembrane protein that is expressed in many tissues throughout development and adult life. It is located in focal adhesions of cultured fibroblasts and other cells and in the adhesive structures of tissues. To further characterize the function of this protein, we generated transgenic mice overexpressing it. High transgene expression was detected in cartilage and bone in locations also containing the endogenous protein.
Materials and Methods: Col13a1 5′-flanking sequences were tested for their efficiencies to drive gene expression. Skeletal tissues of transgenic mice and wildtype littermates were compared using histological, immunohistochemical, and bone histomorphometrical analyses. Bone formation rate was measured by tetracycline double-labeling. Osteoclast number and resorption activity were determined using standard methods. RNA samples from transgenic and wildtype femurs were analyzed by Northern blotting and quantitative RT-PCR.
Results: There was no defect in early skeletal development, but the high bone mass phenotype became apparent in heterozygous mice at the age of 3-4 weeks. The changes were most noticeable in proximal long bones but were also detectable in calvarial bones. The cortical bone cross-sectional area and the volumetric BMD were highly increased, but the bone marrow was well formed. Histological and histomorphometric analysis showed that trabecular bone volume was not significantly altered. Because of the normal epiphyseal growth plates, the longitudinal growth was not affected. Bone formation rate was several times higher in the overexpression mice than in their normal littermates, whereas the osteoclast number and resorption activity were normal. RNA analysis revealed increased expression in the transcription factor Runx2 and IGF-II, both known to be involved in bone biology.
Conclusion: Overexpression of type XIII collagen in skeletal tissues leads postnatally to an abnormally high bone mass caused by increased bone formation rather than impaired resorption. The findings suggest that type XIII collagen has an important role in bone modeling, and in particular, it may have a function in coupling the regulation of bone mass to mechanical use.
Thapsigargin Modulates Osteoclastogenesis Through the Regulation of RANKL-Induced Signaling Pathways and Reactive Oxygen Species Production
Authors: Yip Kirk Hm , Zheng Ming H , Steer James H , Giardina Tindaro M , Han Renzhi , Lo Susan Z , Bakker Anthony J , Cassady A Ian , Joyce David A , Xu Jiake 
Published: April 2006

Abstract
The mechanism by which TG modulates osteoclast formation and apoptosis is not clear. In this study, we showed a biphasic effect of TG on osteoclast formation and apoptosis through the regulation of ROS production, caspase-3 activity, cytosolic Ca2+, and RANKL-induced activation of NF-κB and AP-1 activities.
Introduction: Apoptosis and differentiation are among the consequences of changes in intracellular Ca2+ levels. In this study, we investigated the effects of the endoplasmic reticular Ca2+-ATPase inhibitor, thapsigargin (TG), on osteoclast apoptosis and differentiation.
Materials and Methods: Both RAW264.7 cells and primary spleen cells were used to examine the effect of TG on RANKL-induced osteoclastogenesis. To determine the action of TG on signaling pathways, we used reporter gene assays for NF-κB and activator protein-1 (AP-1) activity, Western blotting for phospho-extracellular signal-related kinase (ERK), and fluorescent probes to measure changes in levels of intracellular calcium and reactive oxygen species (ROS). To assess rates of apoptosis, we measured changes in annexin staining, caspase-3 activity, and chromatin and F-actin microfilament structure.
Results: At concentrations that caused a rapid rise in intracellular Ca2+, TG increased caspase-3 activity and promoted apoptosis in osteoclast-like cells (OLCs). Low concentrations of TG, which were insufficient to measurably alter intracellular Ca2+, unexpectedly suppressed caspase-3 activity and enhanced RANKL-induced osteoclastogenesis. At these lower concentrations, TG potentiated ROS production and RANKL-induced NF-κB activity, but suppressed RANKL-induced AP-1 activity and had little effect on ERK phosphorylation.
Conclusion: Our novel findings of a biphasic effect of TG are incompletely explained by our current understanding of TG action, but raise the possibility that low intensity or local changes in subcellular Ca2+ levels may regulate intracellular differentiation signaling. The extent of cross-talk between Ca2+ and RANKL-mediated intracellular signaling pathways might be important in determining whether cells undergo apoptosis or differentiate into OLCs.
A New Population of Human Adult Dental Pulp Stem Cells: A Useful Source of Living Autologous Fibrous Bone Tissue (LAB)
Authors: Laino Gregorio , D'Aquino Riccardo , Graziano Antonio , Lanza Vladimiro , Carinci Francesco , Naro Fabio , Pirozzi Giuseppe , Papaccio Gianpaolo 
Published: April 2006

Abstract
Stem cells, derived from human adult dental pulp of healthy subjects 30-45 years of age, were cultured, and cells were selected using a FACSorter. A new c-kit+/CD34+/CD45− cell population of stromal bone producing cells (SBP/DPSCs) was selected, expanded, and cultured. These SBP/DPSCs are highly clonogenic and, in culture, differentiate into osteoblast precursors (CD44+/RUNX-2+), still capable of self-renewing, and then in osteoblasts, producing, in vitro, a living autologous fibrous bone (LAB) tissue, which is markedly positive for several bone antibodies. This tissue constitute an ideal source of osteoblasts and mineralized tissue for bone regeneration. In fact, after in vivo transplantation into immunocompromised rats, LAB formed lamellar bone-containing osteocytes.
Introduction: Recently it has been reported that human dental pulp stem cells (DPSCs) are detectable, in humans, only up to the age of 30 years and that they are able to produce in vitro only sporadic calcified nodules and to form, after transplantation in vivo, a mineralized tissue.
Materials and Methods: Stem cells, derived from human adult dental pulp of healthy subjects 30-45 years of age, were cultured, and cells were selected using a FACSorter. Light microscope, histochemistry, immunofluorescence, and RT-PCR analyses were performed to study both stem and differentiating cells.
Results and Conclusions: A new c-kit+/CD34+/CD45− cell population of stromal bone producing cells (SBP/DPSCs) has been selected by FACSorting, expanded, and cultured. These SBP/DPSCs are highly clonogenic and, in culture, differentiate into osteoblast precursors (CD44+/RUNX-2+), still capable of self-renewing, and in osteoblasts, producing, in vitro, a living autologous fibrous bone (LAB) tissue. This new-formed tissue is markedly positive for several antibodies for bone, including osteonectin, bone sialoprotein, osteocalcin, fibronectin, collagen III, and bone alkaline phosphatase (BALP). Cells producing LAB can be stored at −80°C for a long period of time and are an extraordinary source of osteoblasts and mineralized fibrous bone tissue. In this study, we also showed that, in aged humans, stem cells can be detected from their pulps. The produced LAB is a fibrous bone tissue resembling the human bone during mineralization, with an external layer formed by osteoblasts markedly positive for osteocalcin. This newly formed tissue constitute an ideal source of osteoblasts and mineralized tissue for bone regeneration. In fact, after in vivo transplantation into immunocompromised rats, LAB formed lamellar bone containing osteocytes.
Relationship Between Bone Morphology and Bone Quality in Male Tibias: Implications for Stress Fracture Risk
Authors: Tommasini Steven M , Nasser Philip , Schaffler Mitchell B , Jepsen Karl J 
Published: April 2006

Abstract
Biomechanical properties were assessed from the tibias of 17 adult males 17-46 years of age. Tissue-level mechanical properties varied with bone size. Narrower tibias were comprised of tissue that was more brittle and more prone to accumulating damage compared with tissue from wider tibias.
Introduction: A better understanding of the factors contributing to stress fractures is needed to identify new prevention strategies that will reduce fracture incidence. Having a narrow (i.e., more slender) tibia relative to body mass has been shown to be a major predictor of stress fracture risk and fragility in male military recruits and male athletes. The intriguing possibility that slender bones, like those shown in animal models, may be composed of more damageable material has not been considered in the human skeleton.
Materials and Methods: Polar moment of inertia, section modulus, and antero-posterior (AP) and medial-lateral (ML) widths were determined for tibial diaphyses from 17 male donors 17-46 years of age. A slenderness index was defined as the inverse ratio of the section modulus to tibia length and body weight. Eight prismatic cortical bone samples were generated from each tibia, and tissue-level mechanical properties including modulus, strength, total energy, postyield strain, and tissue damageability were measured by four-point bending from monotonic (n = 4/tibia) and damage accumulation (n = 4/tibia) test methods. Partial correlation coefficients were determined between each geometrical parameter and each tissue-level mechanical property while taking age into consideration.
Results: Significant correlations were observed between tibial morphology and the mechanical properties that characterized tissue brittleness and damageability. Positive correlations were observed between measures of bone size (AP width) and measures of tissue ductility (postyield strain, total energy), and negative correlations were observed between bone size (moment of inertia, section modulus) and tissue modulus.
Conclusions: The correlation analysis suggested that bone morphology could be used as a predictor of tissue fragility and stress fracture risk. The average mechanical properties of cortical tissue varied as a function of the overall size of the bone. Therefore, under extreme loading conditions (e.g., military training), variation in bone quality parameters related to damageability may be a contributing factor to the increased risk of stress fracture for individuals with more slender bones.
Effect of Hormone Replacement, Alendronate, or Combination Therapy on Hip Structural Geometry: A 3-Year, Double-Blind, Placebo-Controlled Clinical Trial
Authors: Greenspan Susan L , Beck Thomas J , Resnick Neil M , Bhattacharya Rajib , Parker Robert A 
Published: April 2006

Abstract
This study examined the effect of hormone replacement, alendronate, or combination therapy on hip structural geometry in 373 postmenopausal women over 3 years. We found that antiresorptive agents alone or in combination result in improvement in parameters of hip structural geometry and BMD. These data provide additional information regarding potential mechanisms for fracture reduction with antiresorptive therapy.
Introduction: Fracture reduction is only partially explained by increased BMD. The aim of this study was to examine changes in structural geometry of the hip, derived from DXA in postmenopausal women after treatment with antiresorptive agents.
Materials and Methods: This was a double-blind, placebo-controlled, randomized clinical trial of 373 women over the age of 65 years, who were randomized to hormone replacement therapy, alendronate, combination therapy, or placebo for 3 years. The outcomes included the DXA-derived hip structure analysis program by Beck, which is an engineering interpretation of the DXA data. The indices included cross-sectional area, section modulus (a measure of bending strength), outer diameter, cortical thickness, and buckling ratio (an index of cortical bone stability). Properties were measured in cross-sectional regions traversing the femur at the narrowest point on the femoral neck, the intertrochanteric region, and the proximal shaft.
Results: In the femoral neck, improvement in the hip structure analysis indices were generally significantly greater with combination therapy than either monotherapy; increases were also greater at the intertrochanter compared with hormone replacement therapy. For example, the section modulus at the intertrochanter and narrow neck increased 10.6% and 10.3%, respectively, with combination therapy, 9.1% and 7.3% with alendronate, 5.8% and 6.9% with hormone replacement therapy, and 3.4% and 3.2% with placebo (p &lt; 0.01 across the four groups). Buckling ratio increased, suggesting decreased stability in the placebo group, whereas there was either no change or significant improvements (p &lt; 0.05) in each active treatment group.
Conclusions: We conclude that changes in the distribution of bone mass underlying the improvements in density with antiresorptive agents in combination or alone have positive effects on structural strength and stability at the proximal femur. This study provides additional information on the potential mechanisms for fracture reduction with antiresorptive agents.
Skeletal Effects of Raloxifene After 8 Years: Results from the Continuing Outcomes Relevant to Evista (CORE) Study
Authors: Siris Ethel S , Harris Steven T , Eastell Richard , Zanchetta Jose R , Goemaere Stefan , Diez-Perez Adolfo , Stock John L , Song Jingli , Qu Yongming , Kulkarni Pandurang M , Siddhanti Suresh R , Wong Mayme , Cummings Steven R 
Published: April 2006

Abstract
In the CORE breast cancer trial of 4011 women continuing from MORE, the incidence of nonvertebral fractures at 8 years was similar between placebo and raloxifene 60 mg/day. CORE had limitations for assessing fracture risk. In a subset of 386 women, 7 years of raloxifene treatment significantly increased lumbar spine and femoral neck BMD compared from the baseline of MORE.
Introduction: The multicenter, double-blind Continuing Outcomes Relevant to Evista (CORE) trial assessed the effects of raloxifene on breast cancer for 4 additional years beyond the 4-year Multiple Outcomes of Raloxifene Evaluation (MORE) osteoporosis treatment trial.
Materials and Methods: In CORE, placebo-treated women from MORE continued with placebo (n = 1286), whereas those previously given raloxifene (60 or 120 mg/day) received raloxifene 60 mg/day (n = 2725). As a secondary endpoint, new nonvertebral fractures were analyzed as time-to-first event in 4011 postmenopausal women at 8 years. A substudy assessed lumbar spine and femoral neck BMD at 7 years, with the primary analysis based on 386 women (127 placebo, 259 raloxifene) who did not take other bone-active agents from the fourth year of MORE and who were ≥80% compliant with study medication in CORE.
Results: The risk of at least one new nonvertebral fracture was similar in the placebo (22.9%) and raloxifene (22.8%) groups (hazard ratio {HR}, 1.00; Bonferroni-adjusted CI, 0.82, 1.21). The incidence of at least one new nonvertebral fracture at six major sites (clavicle, humerus, wrist, pelvis, hip, lower leg) was 17.5% in both groups. Posthoc Poisson analyses, which account for multiple events, showed no overall effect on nonvertebral fracture risk, and a decreased risk at six major nonvertebral sites in women with prevalent vertebral fractures (HR, 0.78; 95% CI, 0.63, 0.96). At 7 years after MORE randomization, the differences in mean lumbar spine and femoral neck BMD with raloxifene were 1.7% (p = 0.30) and 2.4% (p = 0.045), respectively, from placebo. Compared with MORE baseline, after 7 years, raloxifene treatment significantly increased lumbar spine (4.3% from baseline, 2.2% from placebo) and femoral neck BMD (1.9% from baseline, 3.0% from placebo). BMDs were significantly increased from MORE baseline at all time-points at both sites with raloxifene.
Conclusion: Raloxifene therapy had no effect on nonvertebral fracture risk after 8 years, although CORE had limitations for fracture risk assessment. BMD increases were maintained after 7 years of raloxifene.
New QCT Analysis Approach Shows the Importance of Fall Orientation on Femoral Neck Strength
Authors: Carpenter R Dana , Beaupré Gary S , Lang Thomas F , Orwoll Eric S , Carter Dennis R 
Published: April 2006

Abstract
The influence of fall orientation on femur strength has important implications for understanding hip fracture risk. A new image analysis technique showed that the strength of the femoral neck in 37 males varied significantly along the neck axis and that bending strength varied by a factor of up to 2.8 for different loading directions.
Introduction: Osteoporosis is associated with decreased BMD and increased hip fracture risk, but it is unclear whether specific osteoporotic changes in the proximal femur lead to a more vulnerable overall structure. Nonhomogeneous beam theory, which is used to determine the mechanical response of composite structures to applied loads, can be used along with QCT to estimate the resistance of the femoral neck to axial forces and bending moments.
Materials and Methods: The bending moment {My(θ)} sufficient to induce yielding within femoral neck sections was estimated for a range of bending orientations (θ) using in vivo QCT images of 37 male (mean age, 73 years; range, 65–87 years) femora. Volumetric BMD, axial stiffness, average moment at yield (My,avg), maximum and minimum moment at yield (My,max and My,min), bone strength index (BSI), stress-strain index (SSI), and density-weighted moments of resistance (Rx and Ry) were also computed. Differences among the proximal, mid-, and distal neck regions were detected using ANOVA.
Results: My(θ) was found to vary by as much as a factor of 2.8 for different bending directions. Axial stiffness, My,avg, My,max, My,min, BSI, and Rx differed significantly between all femoral neck regions, with an overall trend of increasing axial stiffness and bending strength when moving from the proximal neck to the distal neck. Mean axial stiffness increased 62% between the proximal and distal neck, and mean My,avg increased 53% between the proximal and distal neck.
Conclusions: The results of this study show that femoral neck strength strongly depends on both fall orientation and location along the neck axis. Compressive yielding in the superior portion of the femoral neck is expected to initiate fracture in a fall to the side.