bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Alendronate on the Age-Specific Incidence of Symptomatic Osteoporotic Fractures
Authors: Hochberg Marc C , Thompson Desmond E , Black Dennis M , Quandt Sara A , Cauley Jane , Geusens Piet , Ross Philip D , Baran Dan 
Published: April 2006

Abstract
Analyses of data from 3658 postmenopausal women with osteoporosis enrolled in the Fracture Intervention Trial showed that alendronate is effective in reducing the risk of symptomatic osteoporotic fractures across a spectrum of ages.
Introduction: Most osteoporosis studies examine the relative risk of fracture based on the entire duration of treatment. Because older patients tend to be at higher risk for osteoporosis-related fractures, this analysis examined the effect of alendronate treatment on the relative risk of fracture in terms of the age that patients attained during the study.
Materials and Methods: We studied 3658 postmenopausal women with osteoporosis 55-80 years of age at baseline enrolled in the Fracture Intervention Trial, a large randomized, double-blind, placebo-controlled study. Patients were treated with placebo or with alendronate at a daily dose of 5 mg for 2 years followed by 10 mg for an additional 1-2.5 years, and monitored for clinical fractures. Age, rather than study time, was the dynamic variable in our analysis.
Results: The relative risk reductions for hip, clinical spine, and wrist fractures were constant across age groups, without evidence of a decline at older ages. Specifically, alendronate reduced the risk of clinical fracture by 53% at the hip (relative risk [RR] = 0.47; 95% CI = 0.27-0.81; p &lt; 0.01), 45% at the spine (RR = 0.55; 95% CI = 0.37-0.83; p &lt; 0.01), and 31% at the wrist (RR = 0.69; 95% CI = 0.50-0.98; p = 0.038). In addition, alendronate produced a significant risk reduction of 40% (RR = 0.60; 95% CI = 0.47-0.77; p &lt; 0.01) for the composite event of clinical hip, spine, and wrist fractures. As a consequence of the constant relative risk model, the absolute risk reduction with alendronate treatment increased with age because of the age-related increase in fracture risk in the placebo group. The absolute risk reduction for the composite event (hip, spine, and wrist fractures together) for alendronate treatment versus placebo was 65, 80, 111, and 161 women with fractures per 10,000 PYR for the 55 to &lt;65, 65 to &lt;70, 70 to &lt;75, and 75-85 year age groups, respectively.
Conclusions: These data show that alendronate is effective in reducing the risk of symptomatic osteoporotic fractures across a spectrum of ages. The effectiveness is somewhat greater in patients with femoral neck T score ≤ −2.5 than in those with a T score ≤ −2.0.
Reduced Training Is Associated With Increased Loss of BMD
Authors: Valdimarsson Örnólfur , Alborg Henrik G , Düppe Henrik , Nyquist Fredrik , Karlsson Magnus 
Published: April 2006

Abstract
This 8-year controlled, follow-up study in 66 Swedish soccer women evaluated the effect of training and reduced training on BMD. The players who retired during the follow-up lost BMD in the femoral neck, whereas the controls did not.
Introduction: Physical activity during adolescence increases BMD, but whether the benefits are retained with reduced activity is controversial.
Materials and Methods: At baseline, DXA evaluated BMD in 48 active female soccer players with a mean age of 18.2 ± 4.4 (SD) years, in 18 former female soccer players with a mean age of 43.2 ± 6.2 years and retired for a mean of 9.4 ± 5.3 years, and in 64 age- and sex-matched controls. The soccer women were remeasured after a mean of 8.0 ± 0.3 years, when 35 of the players active at baseline had been retired for a mean of 5.3 ± 1.6 years.
Results and Conclusions: The players still active at follow-up had a higher BMD at baseline than the matched controls in the femoral neck (FN; 1.13 ± 0.19 versus 1.00 ± 0.13 g/cm2; p = 0.02). The yearly gain in BMD during follow-up was higher in the active players than in the controls in the leg (0.015 ± 0.006 versus 0.007 ± 0.012 g/cm2, p = 0.04). The soccer players who retired during follow-up had a higher BMD at baseline than the matched controls in the FN (1.13 ± 0.13 versus 1.04 ± 0.13 g/cm2; p = 0.005). The players that retired during follow-up lost BMD, whereas the controls gained BMD during the study period in the FN (−0.007 ± 0.01 versus 0.003 ± 0.02 g/cm2 yearly; p = 0.01). The soccer players already retired at baseline had higher BMD at study start than the matched controls in the leg (1.26 ± 0.09 versus 1.18 ± 0.10 g/cm2; p = 0.01). The former players who were retired at study start lost BMD, whereas the controls gained BMD during the study period in the trochanter (−0.006 ± 0.01 versus 0.004 ± 0.014 g/cm2 yearly; p = 0.01). This study shows that, in girls, intense exercise after puberty is associated with higher accrual of BMD, and decreased physical activity in both the short-term and long-term perspective is associated with higher BMD loss than in controls.
Growth Hormone Injections Improve Bone Quality in a Mouse Model of Osteogenesis Imperfecta
Authors: King Donna , Jarjoura David , McEwen Heather A , Askew Michael J 
Published: April 2006

Abstract
Systemic growth hormone injections increased spine and femur length in a mouse model of OI. Femur BMC, cross-sectional area, and BMD were increased. Smaller gains were produced in vertebral BMC and cross-sectional area. Biomechanical testing showed improvements to structural and material properties in the femur midshaft, supporting expanded testing of growth hormone therapy in children with OI.
Introduction: Osteoblasts in heterozygous Cola2oim mutant mice produce one-half the normal amounts of the α2 strand of type I procollagen. The mice experience a mild osteogenesis imperfecta (OI) phenotype, with femurs and vertebrae that require less force than normal to break in a biomechanical test.
Materials and Methods: Subcutaneous injections of recombinant human growth hormone (rhGH) or saline were given 6 days per week to oim/+ mice between 3 and 12 weeks of age, in a protocol designed to simulate a trial on OI children.
Results: rhGH injections promoted significant weight gain and skeletal growth compared with saline-treated control animals. Femur and spine lengths were increased significantly. Significant increases at the femur midshaft in cortical BMD (2.2%), BMC (15.5%), and cross-sectional area (13%) were produced by rhGH treatment. Increases in the same cortical bone parameters were measured in the metaphyseal region of the femur and in tail vertebrae, but lumbar vertebrae showed significant increases in BMC (9.6%) and cross-sectional area (10.1%) of trabecular bone. Three-point bending testing documented functional improvements to the femur midshafts. GH treatment produced significant increases in bone stiffness (23.7%), maximum load (30.8%), the energy absorbed by the femurs to the point of maximum load (44.5%), and the energy to actual fracture (40.4%). The ultimate stress endured by the bone material was increased by 14.1%.
Conclusions: Gains in bone length, cross-sectional area, BMD, BMC, structural biomechanical properties, and strength were achieved without directly addressing the genetic collagen defect in the mice. Results support expanded clinical testing of GH injections in children with OI.
Controlled Trial of Pamidronate in Children With Types III and IV Osteogenesis Imperfecta Confirms Vertebral Gains but Not Short-Term Functional Improvement
Authors: Letocha Anne D , Cintas Holly L , Troendle James F , Reynolds James C , Cann Christopher E , Chernoff Edith J , Hill Suvimol C , Gerber Lynn H , Marini Joan C 
Published: April 2006

Abstract
Bisphosphonates have been widely administered to children with OI based on observational trials. A randomized controlled trial of q3m intravenous pamidronate in children with types III and IV OI yielded positive vertebral changes in DXA and geometry after 1 year of treatment, but no further significant improvement during extended treatment. The treated group did not experience significantly decreased pain or long bone fractures or have increased motor function or muscle strength.
Introduction: Bisphosphonates, antiresorptive drugs for osteoporosis, are widely administered to children with osteogenesis imperfecta (OI). Uncontrolled pamidronate trials in OI reported increased BMD, vertebral coronal area, and mobility, and decreased pain. We conducted a randomized controlled trial of pamidronate in children with types III and IV OI.
Materials and Methods: This randomized trial included 18 children (4-13 years of age) with types III and IV OI. The first study year was controlled; 9 children received pamidronate (10 mg/m2/day IV for 3 days every 3 months). Four children in each group also received recombinant growth hormone (rGH) injections (0.06 mg/kg/day for 6 days/week). Seven children in the treatment group received pamidronate for an additional 6-21 months. All patients had L1-L4 DXA, spine QCT, spine radiographs, and musculoskeletal and functional testing.
Results: In the controlled phase, treated patients experienced a significant increase in L1-L4 DXA z score (p &lt; 0.001) and increased L1-L4 midvertebral height (p = 0.014) and total vertebral area (p = 0.003) compared with controls. During extended treatment, DXA z scores and vertebral heights and areas did not increase significantly beyond the 12-month values. Fracture rate decreased significantly in the upper extremities (p = 0.04) but not the lower extremities (p = 0.09) during the first year of treatment. Gross motor function, muscle strength, and pain did not change significantly during the controlled or extended treatment phases.
Conclusions: A controlled trial confirmed the spine benefits of short-term pamidronate treatment in children with types III and IV OI. Pamidronate increased L1-L4 vertebral DXA and decreased vertebral compressions and upper extremity fractures. Vertebral measures did not improve during the extended treatment phase. The treatment group did not experience decreased lower extremity long bone fractures, significant improvement in growth, ambulation, muscle strength, or pain. There was substantial variability in individual response to treatment.
Human Bone Collagen Synthesis Is a Rapid, Nutritionally Modulated Process
Authors: Babraj John A , Smith Kenneth , Cuthbertson Daniel JR , Rickhuss Peter , Dorling James S , Rennie Michael J 
Published: April 2006

Abstract
We developed a direct assay of human bone collagen synthesis using [13C] or [15N] proline and applied it to determine the effects of feeding in young healthy men. Surprisingly, postabsorptive bone collagen synthesis is not sluggish, being ∼0.07%/h more rapid than that of muscle protein, and capable of being stimulated within 4 h of intravenous feeding by 66 ± 13%.
Introduction: All current methods for estimation of bone collagen turnover are indirect, depending on the assay of collagen “markers.” Our aim was to develop a direct method for human bone collagen synthesis to be used to study its physiology and pathology, and specifically, in the first instance, the effect of feeding.
Materials and Methods: We applied, over 2 h, flooding doses of [13C] and [15N] proline to label iliac crest bone collagen in eight young healthy men. The rate of collagen synthesis was determined as the rate of labeling of collagen hydroxyproline (assayed by gas chromatography-combustion-isotope ratio mass spectrometry in collagen extracted by differential solubility) compared with plasma proline labeling (assayed by gas chromatography-mass spectrometry). We also determined (in a second group of eight young healthy men) the effect of intravenous nutrition (glucose, lipid emulsion, and amino acids (in the ratio of 55%:30%:15% energy, respectively).
Results: Free bone proline labeling was 92 ± 6% of that of plasma proline, supporting the flooding dose assumption. Human iliac crest bone collagen is heterogeneous, with NaCl-EDTA, 0.5 M acetic acid, pepsin-acetic acid, and hot water-extractable pools being responsible for ∼1%, 3%, 8%, and 81% of content, respectively. The synthetic rates were 0.58 ± 0.1, 0.24 ± 0.05, 0.07 ± 0.02, and 0.06 ± 0.01%/h, respectively, giving an average rate of ∼0.066%/h. [13C] and [15N] proline gave identical results. Intravenous nutrition caused the disappearance of proline label from the procollagen pool and its increased appearance in the less extractable pools, suggesting nutritional stimulation of collagen processing.
Conclusion: The results show (1) that iliac crest bone collagen synthesis is faster than generally assumed and of the same order as muscle protein turnover and (2) that feeding increases synthesis by ∼66%. Given its ability to detect physiologically meaningful responses, the method should provide a new approach to studying the regulation of bone collagen turnover.
Comparison Insight Bone Measurements by Histomorphometry and μCT
Authors: Chappard Daniel , Retailleau-Gaborit Nadine , Legrand Erick , Baslé Michel Félix , Audran Maurice 
Published: April 2006

Abstract
Morphometric analysis of 70 bone biopsies was done in parallel by μCT and histomorphometry. μCT provided higher results for trabecular thickness and separation because of the 3D shape of these anatomical objects.
Introduction: Bone histomorphometry is used to explore the various metabolic bone diseases. The technique is done on microscopic 2D sections, and several methods have been proposed to extrapolate 2D measurements to the 3D dimension. X-ray μCT is a recently developed imaging tool to appreciate 3D architecture. Recently the use of 2D histomorphometric measurements have been shown to provide discordant results compared with 3D values obtained directly.
Material and Methods: Seventy human bone biopsies were removed from patients presenting with metabolic bone diseases. Complete bone biopsies were examined by μCT. Bone volume (BV/TV), Tb.Th, and Tb.Sp were measured on the 3D models. Tb.Th and Tb.Sp were measured by a method based on the sphere algorithm. In addition, six images were resliced and transferred to an image analyzer: bone volume and trabecular characteristics were measured after thresholding of the images. Bone cores were embedded undecalcified; histological sections were prepared and measured by routine histomorphometric methods providing another set of values for bone volume and trabecular characteristics. Comparison between the different methods was done by using regression analysis, Bland-Altman, Passing-Bablock, and Mountain plots.
Results: Correlations between all parameters were highly significant, but μCT overestimated bone volume. The osteoid volume had no influence in this series. Overestimation may have been caused by a double threshold used in μCT, giving trabecular boundaries less well defined than on histological sections. Correlations between Tb.Th and Tb.Sp values obtained by 3D or 2D measurements were lower, and 3D analysis always overestimated thickness by ∼50%. These increases could be attributed to the 3D shape of the object because the number of nodes and the size of the marrow cavities were correlated with 3D values.
Conclusion: In clinical practice, μCT seems to be an interesting method providing reliable morphometric results in less time than conventional histomorphometry. The correlation coefficient is not sufficient to study the agreement between techniques in histomorphometry. The architectural descriptors are influenced by the algorithms used in 3D.
Fibroblasts Express RANKL and Support Osteoclastogenesis in a COX-2-Dependent Manner After Stimulation With Titanium Particles
Authors: Wei Xiaochao , Zhang Xinping , Zuscik Michael J , Drissi M Hicham , Schwarz Edward M , O'Keefe Regis J 
Published: April 2006

Abstract
Synovial fibroblasts are possible mediators of osteolysis. Fibroblasts respond directly to titanium particles and increase RANKL expression through a COX-2/PGE2/EP4/PKA signaling pathway. Fibroblasts pretreated with titanium or PGE2 stimulated osteoclast formation, showing the functional importance of RANKL induction. Synovial fibroblasts and their activation pathways are potential targets to prevent osteolysis.
Introduction: Bone loss adjacent to the implant is a major cause of joint arthroplasty failure. Although the cellular and molecular response to microscopic wear debris particles is recognized as causative, little is known concerning role of synovial fibroblasts in these events.
Materials and Methods: Murine embryonic fibroblasts and knee synovial fibroblasts in culture stimulated with titanium particles were examined by FACS, real time RT-PCR, Northern blot, and Western blot for expressions of vascular cell adhesion molecule (VCAM)1, RANKL, cyclooxygenase (COX)-1, and COX-2, and the four prostaglandin E2 (PGE2) receptor isoforms. Experiments were performed in the presence and absence of COX inhibitors, protein kinase A (PKA) and protein kinase C (PKC) inhibitors, and various EP receptor agonists. Osteoclast formation was examined in co-cultures of pretreated glutaraldehyde-fixed fibroblasts and primary murine spleen cells treated with macrophage-colony stimulating factor (M-CSF) for 7-days.
Results: TNF-α stimulated VCAM1 expression, consistent with a synovial fibroblast phenotype. Titanium particles stimulated RANKL gene and protein expressions in fibroblasts in a dose-dependent manner. Gene expression was increased 5-fold by 4 h, and protein levels reached a maximum after 48 h. Within 1 h, titanium particles also induced COX-2 mRNA and protein levels, whereas both indomethacin and celecoxib blocked the stimulation of RANKL, suggesting a COX-2-mediated event. Furthermore, PGE2 induced RANKL gene and protein expression and rescued RANKL expression in titanium-treated cultures containing COX-2 inhibitors. Fibroblast cultures pretreated with either PGE2 or titanium particles enhanced osteoclast formation, indicating the functional importance of RANKL induction. EP4 was the most abundant PGE2 receptor isoform, EP1 and EP2 were expressed at low levels, and EP3 was absent. The EP1 selective agonist iloprost and the EP2 selective agonist butaprost minimally stimulated RANKL. In contrast, the EP2 and EP4 agonist misoprostol induced RANKL to a magnitude similar to PGE2. Finally, PKA antagonism strongly repressed RANKL stimulation by PGE2.
Conclusion: Fibroblasts respond directly to titanium particles and increase RANKL expression through a COX-2/PGE2/EP4/PKA signaling pathway. Thus, the synovial fibroblast is important mediator of osteolysis and target for therapeutic strategies.
Smoking and the Risk of Fracture in Older Men
Authors: Olofsson Helena , Byberg Liisa , Mohsen Rawya , Melhus Hakan , Lithell Hans , Michaëlsson Karl 
Published: April 2006

Abstract
The role of smoking on fracture risk in older men was studied within a longitudinal population-based cohort study. Using time-dependent exposure information and analysis, smoking was detected to be a stronger, dose-dependent and a more long lasting risk factor for fracture than has previously been estimated.
Introduction: Although several studies have indicated a negative influence of smoking on fracture risk in women, there are few studies in men. No study in either sex has considered that smoking exposure may vary during follow-up in a cohort study. There is a need for a prospective study with repeated measures to analyze smoking exposure and fracture risk in men.
Materials and Methods: A total of 2322 men, 49-51 years of age, were enrolled in a longitudinal, population-based cohort study. Smoking status and other lifestyle habits were established at baseline and additionally at 60, 70, and 77 years of age. One or more fractures were documented in 272 men during 30 years of follow-up. Cox proportional hazards regression was used to determine the rate ratio (RR) of fracture according to time-dependent smoking habits and covariates.
Results: The overall adjusted fracture risk was increased in current (RR, 2.71; 95% CI, 1.86-3.95) and former smokers (RR, 1.66, 95% CI; 1.18-2.34), and persistent until 30 years after cessation. Among current smokers, the adjusted risk of any fracture increased by 30% (95% CI, 6-58%) for every 5 g of tobacco smoked each day. Smoking duration did not substantially influence fracture risk in either current or former smokers. One-half (52%; 95% CI, 35-65%) of all fractures were attributable to current smoking.
Conclusions: Tobacco smoking seems to be a long-lasting major risk factor for fracture in older men, and the risks depends both on recency of smoking and on the daily amount of tobacco smoked, rather than smoking duration.
Interleukin-11 Receptor Signaling Is Required for Normal Bone Remodeling
Authors: Sims Natalie A , Jenkins Brendan J , Nakamura Akira , Quinn Julian MW , Li Ruili , Gillespie Matthew T , Ernst Matthias , Robb Lorraine , Martin T John 
Published: April 2006

Abstract
IL-6 and -11 regulate bone turnover and have been implicated in estrogen deficiency-related bone loss. In this study, deletion of IL-11 signaling, but not that of IL-6, suppressed osteoclast differentiation, resulting in high trabecular bone volume and reduced bone formation. Furthermore, IL-11 signaling was not required for the effects of estradiol or estrogen deficiency on the mouse skeleton.
Introduction: Interleukin (IL)-6 and -11 stimulate osteoclastogenesis and bone formation in vitro and have been implicated in bone loss in estrogen deficiency. Because of their common use of the gp130 co-receptor signaling subunit, the roles of these two cytokines are linked, and each may compensate for the absence of the other to maintain trabecular bone volume and bone cell differentiation.
Materials and Methods: To determine the interactions in bone between IL-11 and IL-6 in vivo and whether IL-11 is required for normal bone turnover, we examined the bone phenotype of mature male and female IL-11 receptor knockout mice (IL-11Rα1−/−) and compared with the bone phenotype of IL-6−/− mice and mice lacking both IL-6 and IL-11Rα. To determine whether IL-11 is required for the effects of estrogen on trabecular bone, mature IL-11Rα1−/− mice were ovariectomized and treated with estradiol.
Results: In both male and female IL-11Rα1−/− mice, trabecular bone volume was significantly higher than that of wildtype controls. This was associated with low bone resorption and low bone formation, and the low osteoclast number generated by IL-11Rα1−/− precursors was reproduced in ex vivo cultures, whereas elevated osteoblast generation was not. Neither trabecular bone volume nor bone turnover was altered in IL-6−/− mice, and compound IL-6−/−:IL-11Rα1−/− mice showed an identical bone phenotype to IL-11Rα1−/− mice. The responses of IL-11Rα1−/− mice to ovariectomy and estradiol treatment were the same as those observed in wildtype mice.
Conclusions: IL-11 signaling is clearly required for normal bone turnover and normal trabecular bone mass, yet not for the effects of estradiol or estrogen deficiency on the skeleton. In the absence of IL-11Rα, increased trabecular bone mass seems to result from a cell lineage-autonomous reduction in osteoclast differentiation, suggesting a direct effect of IL-11 on osteoclast precursors. The effects of IL-11Rα deletion on the skeleton are not mediated or compensated for by changes in IL-6 signaling.