bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Variation in Bone Growth Patterns Defines Adult Mouse Bone Fragility
Authors: Price Christopher , Herman Brad C , Lufkin Thomas , Goldman Haviva M , Jepsen Karl J 
Published: April 2006

Abstract
Femoral morphology and composition were determined for three inbred mouse strains between ages E18.5 and 1 year. Genotype-specific variation in postnatal, pubertal, and postpubertal growth patterns and mineral accrual explained differences in adult bone trait combinations and thus bone fragility.
Introduction: Fracture risk is strongly regulated by genetic factors. However, this regulation is generally considered complex and polygenic. Therefore, the development of effective genetic-based diagnostic and treatment tools hinges on understanding how multiple genes and multiple cell types interact to create mechanically functional structures. The goal of this study was to connect variability in whole bone mechanical function, including measures of fragility, to variability in the biological processes underlying skeletal development. We accomplished this by testing for variation in bone morphology and composition among three inbred mouse strains from E18.5 to 1 year of age.
Materials and Methods: Mid-diaphyseal cross-sectional areas, diameters, moments of inertia, and ash content were determined for three strains of mice with widely differing adult whole bone femoral mechanical properties (A/J, C57BL/6J, and C3H/HeJ) at E18.5 and postnatal days 1, 7, 14, 28, 56, 112, 182, and 365 (n = 5–15 mice/strain/age).
Results: Significant differences in the magnitude and rate of change in morphological and compositional bone traits were observed among the three strains at each phase of growth, including prenatal, postnatal, pubertal, and adult ages. These genotype-specific variations in growth patterns mathematically determined how variation in adult bone trait combinations and mechanical properties arose. Furthermore, six bone traits were identified that characterize phenotypic variability in femoral growth. These include (1) bone size and shape at postnatal day 1, (2) periosteal and (3) endosteal expansion during early growth, (4) periosteal expansion and (5) endosteal contraction in later growth, and (6) ash content. These results show that genetic variability in adult bone traits arises from variation in biological processes at each phase of growth.
Conclusions: Inbred mice achieve different combinations of adult bone traits through genotype-specific regulation of bone surface activity, growth patterns, and whole bone mineral accrual throughout femoral development. This study provides a systematic approach, which can be applied to the human skeleton, to uncover genetic control mechanisms influencing bone fragility.
VEGF Improves, Whereas sFlt1 Inhibits, BMP2-Induced Bone Formation and Bone Healing Through Modulation of Angiogenesis
Authors: Peng Hairong , Usas Arvydas , Olshanski Anne , Ho Andrew M , Gearhart Brian , Cooper Gregory M , Huard Johnny 
Published: April 2006

Abstract
We studied the interaction between VEGF and BMP2 during bone formation and bone healing. Results indicate that VEGF antagonist inhibited BMP2-elicited bone formation, whereas the delivery of exogenous VEGF enhanced BMP2-induced bone formation and bone healing through modulation of angiogenesis.
Introduction: Angiogenesis is closely associated with bone formation during normal bone development and is important for the bone formation elicited by BMP4. However, it remains unknown whether vascular endothelial growth factor (VEGF) also interacts with other BMPs, especially BMP2, in bone formation and bone healing.
Materials and Methods: For this study, mouse muscle-derived stem cells were transduced to express BMP2, VEGF, or VEGF antagonist (sFlt1). We studied the angiogenic process during endochondral bone formation elicited by BMP2, a prototypical osteogenic BMP. Using radiographic and histologic analyses, we also evaluated the interaction between VEGF and BMP2 during bone formation and bone healing.
Results: Our results indicate that BMP2-elicited bone formation comprises two phases of angiogenesis, with an early phase occurring before the appearance of hypertrophic cartilage, followed by a late phase coupled with the appearance of hypertrophic cartilage. Our finding that the administration of sFlt1, a specific antagonist of VEGF, significantly inhibited BMP2-induced bone formation and the associated angiogenesis indicates that endogenous VEGF activity is important for bone formation. Furthermore, we found that the delivery of exogenous VEGF enhanced BMP2-induced bone formation and bone healing by improving angiogenesis, which in turn led to accelerated cartilage resorption and enhanced mineralized bone formation. Our findings also indicate that the ratio between VEGF and BMP2 influences their synergistic interaction, with a higher proportion of VEGF leading to decreased synergism. Our study also revealed unique VEGF-BMP2 interactions that differ from the VEGF-BMP4 interactions that we have described previously.
Conclusions: This study, along with previously published work, shows that VEGF interacts synergistically with both BMP4 and BMP2 but elicits substantially different effects with these two BMPs.
Manipulation of the Anabolic and Catabolic Responses With OP-1 and Zoledronic Acid in a Rat Critical Defect Model
Authors: Little David G , McDonald Michelle , Bransford Rick , Godfrey Craig B , Amanat Negin 
Published: April 2006

Abstract
Bone repair involves both anabolic and catabolic responses. We hypothesized that anabolic treatment with OP-1 (BMP-7) and anti-catabolic treatment with zoledronic acid could be synergistic. In a rat critical defect, this combination therapy produced significant increases in new bone volume and strength.
Introduction: When used to augment bone healing, osteogenic protein 1 (OP-1/BMP-7) and other BMPs stimulate the anabolic response, inducing osteoblast recruitment, differentiation, and bone production. However, BMPs can also upregulate catabolism by direct stimulation of osteoclasts and indirectly by osteoblasts through RANKL/RANK. We hypothesized that if such osteoclastic upregulation were modulated by zoledronic acid (ZA), the combination of OP-1 and ZA should produce increased new bone over OP-1 alone.
Materials and Methods: Rats with a surgically induced 6-mm femoral critical size defect were separated into five dosing groups: Carrier, Carrier + ZA, OP-1, OP-1 + ZA, and OP-1 + ZA administered 2 weeks after surgery (2W). Carrier ± 50 μg OP-1 was placed in the defect, and 0.1 mg/kg ZA or saline was administered subcutaneously. Bone repair was analyzed by radiographs, QCT, mechanical testing, histology, and histomorphometry.
Results: Carrier alone and Carrier ZA groups did not unite by 8 weeks. Radiological union occurred in all OP-1 groups but was tenuous in some animals treated with OP-1 alone. BMC was increased by 45% in the OP-1 ZA group and 96% in the OP-1 ZA 2W group over OP-1 alone (p &lt; 0.01). Callus volume increased over OP-1 alone by 45% and 86% in the OP-1 ZA and OP-1 ZA 2W groups, respectively (p &lt; 0.01). The increased callus volume in the OP-1 ZA 2W group translated to increases in strength of 107% and stiffness of 148% (p &lt; 0.05). BFR was not significantly different between OP-1 groups regardless of ZA treatment.
Conclusions: ZA treatment significantly increased the BMC, volume, and strength of OP-1-mediated callus in a critical size defect in rats at 8 weeks. Thus, modulation of both anabolic and catabolic responses may optimize the amount and mineral content of callus produced, which could be of clinical benefit in obtaining bone union.
Mapping Quantitative Trait Loci for Cross-Sectional Geometry at the Femoral Neck
Authors: Shen Hui , Long Ji-Rong , Xiong Dong-Hai , Liu Yong-Jun , Liu Yao-Zhong , Xiao Peng , Zhao Lan-Juan , Dvornyk Volodymyr , Zhang Yuan-Yuan , Rocha-Sanchez Sonia , Liu Peng-Yuan , Li Jin-Long , Deng Hong-Wen 
Published: April 2006

Abstract
A genome-wide linkage scan was performed in a sample of 79 multiplex pedigrees to identify genomic regions linked to femoral neck cross-sectional geometry. Potential quantitative trait loci were detected at several genomic regions, such as 10q26, 20p12-q12, and chromosome X.
Introduction: Bone geometry is an important determinant of bone strength and osteoporotic fractures. Previous studies have shown that femoral neck cross-sectional geometric variables are under genetic controls. To identify genetic loci underlying variation in femoral neck cross-sectional geometry, we conducted a whole genome linkage scan for four femoral neck cross-sectional geometric variables in 79 multiplex white pedigrees.
Materials and Methods: A total of 1816 subjects from 79 pedigrees were genotyped with 451 microsatellite markers across the human genome. We performed linkage analyses on the entire data, as well as on men and women separately.
Results: Significant linkage evidence was identified at 10q26 for buckling ratio (LOD = 3.27) and Xp11 (LOD = 3.45) for cortical thickness. Chromosome region 20p12-q12 showed suggestive linkage with cross-sectional area (LOD = 2.33), cortical thickness (LOD = 2.09), and buckling ratio (LOD = 1.94). Sex-specific linkage analyses further supported the importance of 20p12-q12 for cortical thickness (LOD = 2.74 in females and LOD = 1.88 in males) and buckling ratio (LOD = 5.00 in females and LOD = 3.18 in males).
Conclusions: This study is the first genome-wide linkage scan searching for quantitative trait loci underlying femoral neck cross-sectional geometry in humans. The identification of the genes responsible for bone geometric variation will improve our knowledge of bone strength and aid in development of diagnostic approaches and interventions for osteoporotic fractures.
Isopropanolic Extract of Black Cohosh Stimulates Osteoprotegerin Production by Human Osteoblasts
Authors: Viereck Volker , Gründker Carsten , Friess Stephanie C , Frosch Karl-Heinz , Raddatz Dirk , Schoppet Michael , Nisslein Thomas , Emons Günter , Hofbauer Lorenz C 
Published: April 2006

Abstract
An isopropanolic extract (iCR) from the rhizomes of Cimicifuga racemosa (black cohosh) is used an alternative in the treatment of menopausal symptoms, and animal studies suggest positive skeletal effects. iCR stimulated osteoblastic OPG protein secretion by 3- to 5-fold as early as 12 h without affecting RANKL expression. The iCR effect, abrogated by the pure estrogen receptor antagonist ICI 182,780, also enhanced ALP activity (4-fold) and osteocalcin expression (3-fold), possibly contributing to the skeletal effects of black cohosh.
Introduction: Despite its positive effects on the skeleton, estrogen replacement therapy is no longer recommended as first-line therapy for the prevention and treatment of postmenopausal osteoporosis because it increases cardiovascular, thromboembolic, and breast cancer risk. Recently, herbal therapeutics such as an isopropanolic extract (iCR) from the rhizomes of Cimicifuga (=Actaea) racemosa (black cohosh) are gaining interest as an alternative in the treatment of menopausal symptoms. Whereas animal studies in rats suggest positive skeletal effects, the mechanism of its actions on bone cells remain unclear. RANKL is essential for osteoclast formation and activation, while osteoprotegerin (OPG) neutralizes RANKL.
Materials and Methods: In this study, we assessed the effects of iCR on OPG and RANKL mRNA steady-state levels by semiquantitative RT-PCR and on protein production by an ELISA system in human osteoblasts (hOBs).
Results: Under serum-free conditions, treatment with iCR increased OPG mRNA levels and protein secretion of hOBs by 2- to 3-fold in a dose-dependent manner, with a maximum effect at a 106-fold dilution of iCR (p &lt; 0.001) after 24–48 h. Time-course experiments indicated a stimulatory effect of iCR on osteoblastic OPG protein secretion by 3- to 5-fold (p &lt; 0.001) as early as 12 h, whereas RANKL expression was very low and was not found to be modulated by iCR. Of note, the stimulatory effect of iCR on OPG production was abrogated by the pure estrogen receptor antagonist ICI 182,780. Moreover, iCR enhanced two osteoblastic differentiation markers, bone-specific alkaline phosphatase activity and osteocalcin expression, by up to 4- and 3-fold, respectively (p &lt; 0.001).
Conclusions: Our data suggest that iCR enhances differentiation and increases the OPG-to-RANKL ratio of normal human osteoblasts. These effects may contribute to the positive skeletal effects of black cohosh.
Estrogen and Testosterone Use Different Cellular Pathways to Inhibit Osteoclastogenesis and Bone Resorption
Authors: Michael Husheem , Härkönen Pirkko L , Väänänen H Kalervo , Hentunen Teuvo A 
Published: April 2006

Abstract
Using human peripheral blood CD14+ osteoclast precursors, we show that testosterone directly inhibits osteoclast formation and bone resorption at physiological concentrations. Instead, estrogen has no direct effects, whereas its action seems to be mediated through osteoblasts by producing osteoprotegerin. Both estrogen and testosterone acts through their cognate receptors.
Introduction: Estrogen (E2) deficiency is associated with both the development of postmenopausal and senile form of osteoporosis in elderly women. Testosterone (Te) deficiency, on the other hand, may cause osteoporosis in men. In both sexes, osteoporosis is associated with disturbed bone turnover, including increased bone resorption caused by enhanced osteoclast formation and increased osteoclast activity. However, the mechanisms by which E2 or Te act on bone are not fully understood, and one of the central questions is whether these hormones act directly on osteoclast precursors or whether their action is mediated through osteoblastic cells.
Materials and Methods: We cultured human peripheral blood CD14+ osteoclast precursors in the presence of RANKL, macrophage-colony stimulating factor (M-CSF), TNF-α, and dexamethasone to induce them to differentiate into osteoclasts. To study the possible osteoblast-mediated effects, osteoclast precursors were also co-cultured either with human MG-63 or SaOS-2 osteoblast-derived osteosarcoma cells. These cultures were treated with 10−8-10−12 M of E2 or Te for 7 days.
Results: E2 did not have any direct effect on osteoclast formation, whereas testosterone inhibited osteoclast formation and bone resorption in a dose-dependent manner. In co-cultures, where MG-63 or SaOS-2 cells were present, E2 and Te inhibited osteoclast formation in a dose-dependent manner. At the same time, E2 and Te treatment in MG-63 or SaOS-2 cell-containing cultures stimulated significantly the formation of osteoprotegerin (OPG) compared with untreated cultures measured by ELISA assay from the culture medium. The effects of E2 and Te on osteoclast formation and bone resorption were completely antagonized by an E2 receptor (ER) antagonist, ICI 182,780, and an androgen receptor (AR) antagonist, flutamide, suggesting ER- and AR-mediated mechanisms, respectively, in these cultures.
Conclusions: Te is likely to have direct and indirect inhibitory effects on human osteoclast formation and bone resorption, whereas the effect of E2 on osteoclast precursors and osteoclasts seems to be mediated by osteoblastic cells. Inhibitory effect of E2 is associated with the stimulated secretion of OPG by osteoblast-derived osteosarcoma cells. Mechanism of action of E2 and Te is mediated by ER and AR, respectively.
Social Position Affects Bone Mass in Childhood Through Opposing Actions on Height and Weight
Authors: Clark Emma M , Ness Andy , Tobias Jon H 
Published: April 2006

Abstract
We studied relationships between social position of the mother in pregnancy and bone mass of the child at age 9.9 years. The tendency for social position to increase bone area and bone mass through a positive influence on height was opposed by a negative effect of social position on weight and fat mass.
Introduction: Evidence that social factors influence skeletal growth raises the possibility that bone mass acquisition in childhood is socially determined.
Materials and Methods: To clarify the role of social factors in bone mass acquisition in childhood, we studied relationships between these variables in the Avon Longitudinal Study of Parents and Children (ALSPAC). Measures of the mother's social position during pregnancy were linked to DXA results obtained at age 9.9 years in 6702 children. Linear regression analyses were carried out after adjusting for age and gender. Because social position may affect height and weight of the child, analyses were repeated after adjusting for these additional variables.
Results: Measures of social position in pregnancy were unrelated to total body BMC in analyses adjusted for age and gender alone. However, after adjusting for height, which was positively related to social position, a strong negative association was observed between BMC and housing tenure (p &lt; 0.001), maternal education (p &lt; 0.001), paternal education (p &lt; 0.001), and social class (p &lt; 0.001). Similar results were obtained for bone area. After adjusting for weight as well as height, an association between social position and BMC and bone area was no longer observed. Hence, social position seems to exert opposing height- and weight-dependent effects on BMC and bone area in childhood. In further analyses, we found that adjusting for fat mass of the child led to similar results to those obtained with weight.
Conclusions: Social position in childhood seems to be positively related to bone mass acquisition in childhood as a consequence of enhanced gain in height (i.e., longitudinal growth). However, this influence is counteracted by the tendency for increased fat deposition in those from a lower social position to increase bone area, presumably reflecting the stimulation of appositional bone growth.
Sympathetic Nervous System Does Not Mediate the Load-Induced Cortical New Bone Formation
Authors: de Souza Roberto L , Pitsillides Andrew A , Lanyon Lance E , Skerry Timothy M , Chenu Chantal 
Published: April 2006

Abstract
The contribution of the SNS to bone's response to mechanical loading is unclear. Using a noninvasive model of axial loading of the murine tibia, we found that sciatic neurectomy enhances load-induced new cortical bone formation and that pharmacological blockade of the SNS does not affect such responses, indicating that the SNS does not mediate the osteogenic effects of loading in cortical bone.
Introduction: There is increasing evidence that the sympathetic nervous system (SNS) contributes to the regulation of bone mass and may influence remodeling by modulating bones' response to mechanical load-bearing. The aim of this study was to examine the effect of sciatic neurectomy (SN) on the changes in cortical bone formation induced in response to mechanical loading and to investigate whether the SNS is directly involved in such load-induced responses.
Materials and Methods: Accordingly, load-induced responses were compared in tibias of growing and adult control C57Bl/J6 mice and in mice submitted to unilateral SN; noninvasive axial loading that induced 2000 μstrain on the tibia lateral midshaft cortex was applied cyclically, 5 or 100 days after surgery, for 7 minutes, 3 days/week for 2 weeks, and mice received calcein on the third and last days of loading. Tibias were processed for histomorphometry, and transverse confocal images from diaphyseal sites were analyzed to quantify new cortical bone formation. Chemical SNS inactivation was achieved by prolonged daily treatment with guanethidine sulfate (GS) or by the introduction of propranolol in drinking water.
Results: Our results show that new cortical bone formation is enhanced by loading in all tibial sites examined and that load-induced periosteal and endosteal new bone formation was greater in the SN groups compared with sham-operated controls. This SN-related enhancement in load-induced cortical bone formation in tibias was more pronounced 100 days after neurectomy than after 5 days, suggesting that longer periods of immobilization promote a greater sensitivity to loading. In contrast, the increases in new bone formation induced in response to mechanical loading were similar in mice treated with either GS or propranolol compared with controls, indicating that inactivation of the SNS has no effect on load-induced cortical new bone formation.
Conclusions: This study shows that SN, or the absence of loading function it entails, enhances loading-related new cortical bone formation in the tibia independently of the SNS.
Safety and Efficacy of Risedronate in Patients With Age-Related Reduced Renal Function as Estimated by the Cockcroft and Gault Method: A Pooled Analysis of Nine Clinical Trials
Authors: Miller Paul D , Roux Christian , Boonen Steven , Barton Ian P , Dunlap Lisa E , Burgio David E 
Published: April 2006

Abstract
The incidences of osteoporosis and renal insufficiency increase with age. We studied the influence of renal function on the safety and efficacy of risedronate 5 mg daily in osteoporotic women. Risedronate was safe and effective in osteoporotic women with mild, moderate, or severe age-related renal impairment.
Introduction: The incidences of both osteoporosis and renal insufficiency increase with age; thus, the effect of renal impairment on the safety and efficacy of osteoporosis treatments is a clinical concern. Risedronate is a pyridinyl bisphosphonate well established as safe and effective in the treatment and prevention of osteoporosis. Currently, there is little available information about the effect of bisphosphonate treatment in patients with renal insufficiency. This retrospective analysis was conducted to study the influence of renal function on the safety and efficacy of risedronate in a population of osteoporotic women.
Materials and Methods: Combined data from nine randomized, double-blind, placebo-controlled phase III risedronate trials were analyzed. The patients in these studies had no markedly abnormal laboratory parameters that were considered clinically significant and no evidence of significant disease. This analysis included patients who received placebo (n = 4500) or risedronate 5 mg (n = 4496) for up to 3 years (average duration of exposure, 2 years) and who had renal impairment (creatinine clearance [CrCl] &lt; 80 ml/min). CrCl was estimated by the Cockcroft and Gault method, based on age, weight, and serum creatinine. Patients were categorized as having mild (CrCl ≥50 to &lt;80 ml/min), moderate (CrCl ≥30 to &lt;50 ml/min), or severe (CrCl &lt; 30 ml/min) renal impairment.
Results: Of the patients studied, renal impairment at baseline was mild in 48% (mean [range] serum creatinine, 0.9 [0.4–1.6] mg/dl), moderate in 45% (1.1 [0.6–1.9] mg/dl), and severe in 7% (1.3 [0.7–2.7] mg/dl). In both the placebo and risedronate treatment groups, the patients with the most severe renal impairment were older and had more severe osteoporosis. The incidences of overall adverse events and of renal function-related adverse events were similar in the placebo and risedronate 5 mg groups regardless of renal function. Furthermore, evaluation of changes from baseline in serum creatinine revealed no difference in renal function between the placebo and risedronate 5 mg groups in any of the renal impairment subgroups at any time-point. In all three subgroups, risedronate effectively preserved BMD and reduced the incidence of vertebral fractures.
Conclusions: These findings show that risedronate is safe and effective in osteoporotic women with age-related mild, moderate, or severe renal impairment.