bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Crohn's Disease on Bone Metabolism In Vitro: A Role for Interleukin-6
Authors: Sylvester Francisco A. , Wyzga Nancy , Hyams Jeffrey S. , Gronowicz Gloria A. 
Published: April 2006

Abstract
Circulating proinflammatory cytokines may be involved in osteopenia associated with Crohn's disease (CD). Therefore, the effect of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF) α contained in Crohn's serum on bone formation was examined in a bone organ culture system. Initially, serum levels of IL-6, IL-1β, and TNF-α were determined by ELISA in newly diagnosed, untreated children with CD and healthy age-matched controls. Serum IL-6 levels were significantly higher in patients with CD than in controls (23.9 ± 2.8 pg/ml vs. 0.7 pg/ml ± 0.2; p &lt; 0.001), whereas IL-1β and TNF-α serum levels were not. In the organ culture studies, 20-day-old fetal rat parietal bones were incubated for 96 h with CD or control serum, serum preincubated with a neutralizing antibody to each cytokine or a nonimmune immunoglobulin control, and with IL-6. Bone formation measured by assaying calcium content and dry weight was significantly decreased in bones exposed to Crohn's serum. Light microscopy of the bones treated with CD serum revealed a discontinuous, uneven mineralized bone matrix and disorganized osteoblasts with altered morphology. Incubation with an antibody that neutralized IL-6 activity prevented the change in osteoblast and bone morphology. TNF-α and IL-1β antibodies had no apparent effects. Collagen synthesis and DNA content were not affected by CD serum. Also, addition of IL-6 to the culture medium decreased mineralization. These results suggest that IL-6 is a mediator of the effects of Crohn's serum on in vitro mineralization and may be a contributing factor to the osteopenia associated with CD.
Adjusting Bone Mass for Differences in Projected Bone Area and Other Confounding Variables: An Allometric Perspective
Authors: Nevill Alan M. , Holder Roger L. , Maffulli Nicola , Cheng Jack C. Y. , Leung Sophie S. S. F. , Lee Warren T. K. , Lau Joseph T. F. 
Published: April 2006

AbstractThe traditional method of assessing bone mineral density (BMD; given by bone mineral content [BMC] divided by projected bone area [Ap], BMD = BMC/Ap) has come under strong criticism by various authors. Their criticism being that the projected bone “area” (Ap) will systematically underestimate the skeletal bone “volume” of taller subjects. To reduce the confounding effects of bone size, an alternative ratio has been proposed called bone mineral apparent density [BMAD = BMC/(Ap)3/2]. However, bone size is not the only confounding variable associated with BMC. Others include age, sex, body size, and maturation. To assess the dimensional relationship between BMC and projected bone area, independent of other confounding variables, we proposed and fitted a proportional allometric model to the BMC data of the L2-L4 vertebrae from a previously published study. The projected bone area exponents were greater than unity for both boys (1.43) and girls (1.02), but only the boy's fitted exponent was not different from that predicted by geometric similarity (1.5). Based on these exponents, it is not clear whether bone mass acquisition increases in proportion to the projected bone area (Ap) or an estimate of projected bone volume (Ap)3/2. However, by adopting the proposed methods, the analysis will automatically adjust BMC for differences in projected bone size and other confounding variables for the particular population being studied. Hence, the necessity to speculate as to the theoretical value of the exponent of Ap, although interesting, becomes redundant.
Universal Standardization of Forearm Bone Densitometry
Authors: Shepherd John A. , Cheng Xiao Guang , Lu Ying , Njeh Chris , Toschke Jorg , Engelke Klaus , Grigorian Michael , Genant Harry K. 
Published: April 2006

Abstract
As part of an effort to quantify device-dependent differences in forearm bone density, 101 women, aged 20-80 years (∼16 women in each age decade), were scanned on six forearm bone densitometers: the Aloka DCS-600EX, the Hologic QDR-4500A, the Lunar PIXI, the Norland pDEXA, the Osteometer DTX-200, and the Pronosco X-posure System. Regression statistics are reported for all similar regions of interest (ROIs). However, comparisons were confounded because of large differences in the ROI size and placement. The number of ROIs reported for a single scan by each device varied from 1 to 12. The correlation coefficients ranged from 0.7 &lt; r &lt; 0.97, with the highest correlation coefficients and lowest SEs for comparisons between the most similar ROIs. Standardized units of bone mineral density are derived for distal (sdBMD), mid- (smBMD), and proximal (spBMD) ROIs that allow for comparable mean bone densities to be derived for patient populations. Five phantoms were scanned and characterized on five of the devices and the precision and mean values were reported. These phantom values will aid in the in vitro cross-calibration between manufacturers to recreate the presented in vivo relationships. Care should be exercised when using these equations for cross-calibrating patient databases or pooling clinical data from different devices because the least significant differences detectable from measurements taken on two different machines can be increased substantially.
Synchrotron Radiation Microtomography Allows the Analysis of Three-Dimensional Microarchitecture and Degree of Mineralization of Human Iliac Crest Biopsy Specimens: Effects of Etidronate Treatment
Authors: Nuzzo S. , Lafage-Proust M. H. , Martin-Badosa E. , Boivin G. , Thomas T. , Alexandre C. , Peyrin F. 
Published: April 2006

Abstract
Quantitative microcomputed tomography using synchrotron radiation (SR μCT) was used to assess the effects of a sequential etidronate therapy on both three-dimensional (3D) microarchitecture and degree of mineralization of bone (DMB) in postmenopausal osteoporosis. Thirty-two iliac crest biopsy specimens were taken from 14 patients with osteoporosis (aged 64 ± 1.8 years) before (baseline) and after 1 year of etidronate treatment, and after 2 years of treatment for four of the patients. The samples were imaged at high spatial resolution (voxel size = 10 μm) using the microtomography system developed at the European Synchrotron Radiation Facility (ESRF), Grenoble, France. Three-dimensional microarchitecture parameters were calculated and compared with those obtained from conventional histomorphometry. In addition, the DMB was evaluated also in 3D. No significant statistical changes regarding bone mass and structural parameters were observed in histomorphometry or 3D analyses. The distribution of the DMB in cortical and trabecular bone showed a trend to a shift toward highest mineralization values after 1 year of etidronate treatment (3.88% and 1.24% in cortical and trabecular bone, respectively). This trend was more evident after 2 years. The study also showed that SR μCT is an accurate technique and the only one for quantifying both the mineralization and the microarchitecture of bone samples at the same time in 3D.
Bone Morphogenetic Protein 2 Induces Cyclo-oxygenase 2 in Osteoblasts via a Cbfa1 Binding Site: Role in Effects of Bone Morphogenetic Protein 2 In Vitro and In Vivo
Authors: Chikazu Daichi , Li Xiaodong , Kawaguchi Hiroshi , Sakuma Yoko , Voznesensky Olga S. , Adams Douglas J. , Xu Manshan , Hoshi Kazuto , Katavic Vedran , Herschman Harvey R. , Raisz Lawrence G. , Pilbeam Carol C. 
Published: April 2006

Abstract
We tested the hypothesis that induction of cyclo-oxygenase (COX) 2 mediates some effects of bone morphogenetic protein (BMP) 2 on bone. BMP-2 induced COX-2 mRNA and prostaglandin (PG) production in cultured osteoblasts. BMP-2 increased luciferase activity in calvarial osteoblasts from mice transgenic for a COX-2 promoter-luciferase reporter construct (Pluc) and in MC3T3-E1 cells transfected with Pluc. Deletion analysis identified the −300/−213-bp region of the COX-2 promoter as necessary for BMP-2 stimulation of luciferase activity. Mutation of core-binding factor activity 1 (muCbfa1) consensus sequence (5′-AACCACA-3′) at −267/−261 bp decreased BMP-2 stimulation of luciferase activity by 82%. Binding of nuclear proteins to an oligonucleotide spanning the Cbfa1 site was inhibited or supershifted by specific antibodies to Cbfa1. In cultured osteoblasts from calvariae of COX-2 knockout (−/−) and wild-type (+/+) mice, the absence of COX-2 expression reduced the BMP-2 stimulation of both ALP activity and osteocalcin mRNA expression. In cultured marrow cells flushed from long bones, BMP-2 induced osteoclast formation in cells from COX-2+/+ mice but not in cells from COX-2−/− mice. In vivo, BMP-2 (10 μg/pellet) induced mineralization in pellets of lyophilized collagen implanted in the flanks of mice. Mineralization of pellets, measured by microcomputed tomography (μCT), was decreased by 78% in COX-2−/− mice compared with COX-2+/+ mice. We conclude that BMP-2 transcriptionally induces COX-2 in osteoblasts via a Cbfa1 binding site and that the BMP-2 induction of COX-2 can contribute to effects of BMP-2 on osteoblastic differentiation and osteoclast formation in vitro and to the BMP-2 stimulation of ectopic bone formation in vivo.
Localization of Nitric Oxide Synthases During Fracture Healing
Authors: Zhu Wei , Murrell George A. C. , Lin Jianhao , Gardiner Edith M. , Diwan Ashish D. 
Published: April 2006

Abstract
Previously, we have reported that nitric oxide synthases (NOSs), which generate NO, modulate fracture healing. However, the cellular sources of the NOS isoforms during the course of fracture healing have not been studied systematically. The purpose of this study was to localize the cellular distribution of NOS isoforms (inducible NOS [iNOS], endothelial NOS [eNOS], and neuronal NOS [bNOS]) by in situ hybridization and immunohistology after femoral fractures in rats. The iNOS signal was detected during the initial stages (on day 4 and day 7) of fracture healing in 52 ± 2% (mean ± SE, n = 7) of cells within the intramembranous region, along the edge of the periosteal callus. The iNOS signal in callus cells declined to an undetectable level on day 14. eNOS was detected during the middle stages (on day 7 and day 14) of fracture healing in cells lining the blood vessels and also in 49 ± 3% of cells in the chondral region. The bNOS signal was found to be increased at the later stages (day 14 and day 21) of fracture healing in 51 ± 3% of cells at the junction between fibrous tissue and cartilage within the fibrochondral region. In summary, the expression of NOS isoforms during fracture healing was time dependent and cellular distinctive.
The Comparative Efficacy of Drug Therapies Used for the Management of Corticosteroid-Induced Osteoporosis: A Meta-Regression
Authors: Amin Shreyasee , Lavalley Michael P. , Simms Robert W. , Felson David T. 
Published: April 2006

Abstract
We determined the comparative efficacy of vitamin D, calcitonin, fluoride, and bisphosphonates for the management of corticosteroid-induced osteoporosis using meta-regression models. A systematic search for trials was conducted using MEDLINE, bibliographic references, abstracts from national meetings, and contact with pharmaceutical companies and content experts. We included all randomized controlled trials, lasting at least 6 months, of adult patients on oral corticosteroids that evaluated treatment comparisons between vitamin D, calcitonin, bisphosphonates, or fluoride either with no therapy/calcium or with each other and that reported extractable results. The outcome measure of interest was change in lumbar spine bone mineral density (BMD). We identified 45 eligible trials, which provided 49 eligible treatment comparisons (some trials had three arms or more). Our results indicated that bisphosphonates were the most effective class (effect size 1.03; 95% CI: 0.85, 1.17); results were similar even when newer generations of nitrogen-containing bisphosphonates were excluded from analysis. We found the efficacy of bisphosphonates was enhanced further when used in combination with vitamin D (effect size, 1.31; 95% CI: 1.07, 1.50). Vitamin D and calcitonin were more effective than no therapy/calcium (effect size, 0.46; 95% CI: 0.27, 0.62; and effect size, 0.51; 95% CI: 0.33, 0.67, respectively) and were of similar efficacy, but both were significantly less effective than bisphosphonates. Fluoride appeared effective, but there were too few studies (n = 5) to draw robust conclusions regarding its efficacy compared with the other three therapies. In summary, bisphosphonates are the most effective of evaluated agents for managing corticosteroid-induced osteoporosis. The efficacy of bisphosphonates is enhanced further with concomitant use of vitamin D.
Insulin‐Like Growth Factor I Effect on the Number of Osteoblast Progenitors Is Impaired in Ovariectomized Mice
Authors: Kasukawa Yuji , Stabnov Lisa , Miyakoshi Naohisa , Baylink David J. , Mohan Subburaman 
Published: April 2006

AbstractBecause insulin‐like growth factor (IGF) I is an important regulator of bone formation, we proposed the hypothesis that IGF‐I could contribute in regulating the number of osteoblast progenitors (colony‐forming unit fibroblast with ALP activity [CFU‐F/ALP+]). To test ex vivo and in vivo effects of IGF‐I on the number of CFU‐F/ALP+, bone marrow cells (BMCs) derived from normal mice, growth hormone (GH)‐deficient lit/lit mice, or ovariectomized (OVX) mice were cultured and the CFU‐F/ALP+ number was counted. Ex vivo treatment of IGF‐I increased the CFU‐F/ALP+ number in a dose‐dependent manner compared with vehicle‐treated control cultures. The CFU‐F/ALP+ number was decreased by 20% (p < 0.01; n = 7−9) in GH‐deficient lit/lit mice compared with age‐matched control mice. Four weeks after OVX or sham operation, IGF‐I (2 μg/g body wt) or vehicle was administered twice on day 1, and 5 days later, BMCs were removed from the femur and cultured for 10 days (n = 9−10 per group). IGF‐I administration increased the CFU‐F/ALP+ number by 63% (p < 0.01) and 19% (NS), respectively, in sham‐operated (sham) and OVX mice compared with the vehicle‐treated control group. The serum IGF‐I level was similar in OVX mice compared with sham mice; this finding is different from that found in rats in which OVX increases the serum IGF‐I level. This study showed that IGF‐I is an important regulator of osteoblast‐progenitor number in the BMCs of mice both ex vivo and in vivo and that the IGF‐I response to increase the number of osteoblast progenitors was impaired in OVX mice.
Long Bones From the Senescence Accelerated Mouse SAMP6 Have Increased Size But Reduced Whole‐bone Strength and Resistance to Fracture
Authors: Silva Matthew J. , Brodt Michael D. , Ettner Sara L. 
Published: April 2006

AbstractThe senescence accelerated mouse strain P6 (SAMP6) has emerged as a useful model of senile osteoporosis because it has many features of the disease, including low trabecular bone formation and low areal bone density. We further characterized the SAMP6 model of senile osteoporosis by comparing morphological, mechanical, and densitometric properties of femurs and tibias from SAMP6 mice to those of the control strain (SAMR1) at 4 months and 12 months of age. SAMP6 long bones had increased periosteal width and endosteal area (p < 0.05), resulting in an average increase of 30% in moments of inertia (p < 0.05), but no difference in bone area (p > 0.05) compared with control. Despite their increased moments of inertia, long bones from SAMP6 mice were relatively weak and brittle. Ultimate bending moment was reduced by 25%, and both postyield displacement and energy‐to‐fracture were reduced by 60% compared with SAMR1 controls (p < 0.001). Average cortical ash fraction was increased slightly from 0.74 in SAMR1 to 0.76 in SAMP6 bones (p < 0.05), indicating that increased mineralization may have contributed to the brittleness of SAMP6 bones. The relative differences we observed—increased endosteal and periosteal dimensions, reduced bending strength, increased brittleness, and increased mineralization—are analogous to changes that occur in the aging human skeleton. Moreover, these features were consistently observed in young (4‐month) and old (12‐month) animals. These findings extend the previous descriptions of the SAMP6 mouse and identify key mechanical features that further validate its relevance as a unique and functionally relevant model of senile osteoporosis.
Low‐Magnitude Mechanical Loading Becomes Osteogenic When Rest Is Inserted Between Each Load Cycle
Authors: Srinivasan Sundar , Weimer David A. , Agans Steven C. , Bain Steven D. , Gross Ted S. 
Published: April 2006

AbstractStrategies to counteract bone loss with exercise have had fairly limited success, particularly those regimens subjecting the skeleton to mild activity such as walking. In contrast, here we show that it is possible to induce substantial bone formation with low‐magnitude loading. In two distinct in vivo models of bone adaptation, we found that insertion of a 10‐s rest interval between each load cycle transformed a locomotion‐like loading regime that minimally influenced osteoblast activity into a potent anabolic stimulus. In the avian ulna model, the minimal mean (+SE) periosteal labeled surface (Ps.LS) observed in the intact contralateral bones (1.6 ± 1.5%) was doubled after 3 consecutive days of low‐magnitude loading (3.8 ± 1.5%; p = 0.03). However, modifying the regimen by inserting 10 s of rest between each load cycle significantly enhanced the periosteal response (21.9 + 4.5%; p = 0.03). In the murine tibia model, 5 consecutive days of 100 low‐magnitude loading cycles did not significantly alter mean periosteal bone formation rate (BFR) compared with contralateral bones (0.011 ± 0.005 μm3/μm2 per day vs. 0.021 ± 0.013 μm3/μm2 per day). In contrast, separating each of 10 of the same loading cycles with 10 s of rest significantly elevated periosteal BFR (0.167 ± 0.049 μm3/μm2 per day; p = 0.01). Endocortical bone formation parameters were not altered by any loading regimen in either model. We conclude that 10 s of rest between each load cycle of a low‐magnitude loading protocol greatly enhances the osteogenic potential of the regimen.
Long‐Term Predictions of the Therapeutic Equivalence of Daily and Less Than Daily Alendronate Dosing
Authors: Hernandez C. J. , Beaupré G. S. , Marcus R. , Carter D. R. 
Published: April 2006

AbstractLess than daily alendronate dosing has been identified as an attractive alternative to daily dosing for patients and physicians. A recent 2‐year study found bone mineral density (BMD) changes caused by weekly alendronate dosing therapeutically equivalent to that caused by daily dosing. There are no methods that can be used to predict how long therapeutic equivalence will be maintained after the first 2 years of treatment. In addition, it is unclear if dosing less frequently than weekly also might be therapeutically equivalent to daily dosing. In this study we use a computer simulation to develop predictions of the therapeutic equivalence of daily and less than daily dosing over time periods as long as a decade. The computer simulation uses a cell‐based computer model of bone remodeling and a quantitative description of alendronate pharmacokinetics/pharmacodynamics (PK/PD). The analyses suggest that less than daily dosing regimens do not increase BMD as much as daily dosing. However, model predictions suggest that dosing as frequent as weekly still may be therapeutically equivalent to daily dosing over periods as long as 10 years. In addition, the simulations predict dosing less frequently than weekly may be therapeutically equivalent to daily dosing within the first year of treatment but may not be therapeutically equivalent after 10 years. Hypotheses based on these simulations may be useful for determining which dosing regimen may be most attractive for clinical trials.
Cyclic Adenosine Monophosphate/Protein Kinase A Mediates Parathyroid Hormone/Parathyroid Hormone‐Related Protein Receptor Regulation of Osteoclastogenesis and Expression of RANKL and Osteoprotegerin mRNAs by Marrow Stromal Cells
Authors: Kondo Hisatomo , Guo Jun , Bringhurst F. Richard 
Published: April 2006

AbstractParathyroid hormone (PTH) is a major regulator of osteoclast formation and activation, effects that are associated with reciprocal up‐ and down‐regulation of RANKL and osteoprotegerin (OPG), respectively. The roles of specific downstream signals generated by the activated PTH/PTH‐related protein (PTHrP) receptor (PTH1R), such as cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) and phospholipase C/protein kinase C (PLC/PKC), in controlling RANKL and OPG expression and osteoclastogenesis remain uncertain. In MS1 conditionally transformed clonal murine marrow stromal cells, which support PTH‐induced osteoclast formation from cocultured normal spleen cells, PTH(1–34) increased RANKL and macrophage colony‐stimulating factor (M‐CSF) mRNA expression and decreased that of OPG when present continuously for 7–20 days at 37°C in the presence of dexamethasone (Dex). In cells precultured for 7 days and then treated with PTH(1–34), similar reciprocal regulation of RANKL and OPG occurred, maximally at 6–24 h, that was of greater amplitude than the changes induced by chronic (7–10 days) PTH exposure. These acute effects of PTH(1–34) were mimicked by PKA stimulators (8‐bromoadenosine [8Br]‐cAMP or forskolin [FSK]), blocked by the PKA inhibitor Rp‐cAMPs but unaffected by the PKC inhibitor GF109203X. Amino‐truncated PTH(1–34) analogs PTH(5–34) and PTH(7–34) neither increased cAMP production in MS1 cells nor regulated RANKL or OPG mRNA. Reciprocal RANKL/OPG mRNA regulation was induced in MS1 cells by PTH(3–34) but only at high concentrations that also increased cAMP. The highly PKA‐selective PTH analog [Gly1,Arg19]human PTH(1–28) exerted effects similar to PTH(1–34) on RANKL and OPG mRNAs and on osteoclast formation, both in MS1/spleen cell cocultures and in normal murine bone marrow cultures. The direct PKC stimulator 12‐O‐tetradecanoylphorbol‐13‐acetate (PMA) did not induce RANKL mRNA in MS1 cells, but it did up‐regulate OPG mRNA and also antagonized osteoclast formation induced by PTH(1–34) in both MS1/spleen cocultures and normal bone marrow cultures. Thus, cAMP/PKA signaling via the PTH1R is the primary mechanism for controlling RANKL‐dependent osteoclastogenesis, although direct PKC activation may negatively regulate this effect of PTH by inducing expression of OPG.