bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hip Fracture Patients at Risk of Second Hip Fracture: A Nationwide Population-Based Cohort Study of 169,145 Cases During 1977–2001
Authors: Ryg Jesper , Rejnmark Lars , Overgaard Soren , Brixen Kim , Vestergaard Peter 
Published: March 2009

Abstract
In patients with prior hip fracture (HFx), little is known about time frame and risk factors of second HFx, as well as the ensuing mortality. The aim of the study was to elucidate the incidence of second HFx and subsequent mortality. All 169,145 patients with a first HFx in Denmark during 1977–2001 were followed for up to 25 yr and compared with the background population. Data on fractures, vital status, comorbidity, redeemed prescriptions, and socio-demographic variables were retrieved from national registers. Median follow-up was 3.8 yr, corresponding to 1,041,177 patient-years. A total of 27,834 patients had a second HFx. The cumulative incidence was 9% after 1 yr and 20% after 5 yr, being significantly higher than expected (2% and 12%, respectively; p &lt; 0.05). The RR of second HFx was 2.2 (95% CI: 2.0–2.5) at 1 yr and did not normalize until 15 yr (RR = 1.01, 95% CI: 1.0–1.02). Risk factors for a second HFx were female sex (HR = 1.36, 95% CI: 1.32–1.40), age (HR = 1.68, 95% CI: 1.60–1.76 in patients &gt;85 yr), alcoholism (HR = 1.61, 95% CI: 1.51–1.72), any prior fracture (HR = 1.08, 95%CI :1.04–1.11), and living alone (HR = 1.06, 95% CI: 1.04–1.09). Both sexes had higher mortality at 1 and 5 yr after a second HFx compared with the background population (men—1 yr: 27% versus 9%, p &lt; 0.05; 5 yr: 64% versus 40%, p &lt; 0.05; women—1 yr: 21% versus 10%, p &lt; 0.05; 5 yr: 58% versus 41%, p &lt; 0.05). Patients with HFx are at 2-fold risk of further HFx and the subsequent mortality is highly increased. We propose that programs for secondary prevention should be developed and tested.
Elevated Aromatase Expression in Osteoblasts Leads to Increased Bone Mass Without Systemic Adverse Effects
Authors: Sjögren Klara , Lagerquist Marie , Moverare-Skrtic Sofia , Andersson Niklas , Windahl Sara H , Swanson Charlotte , Mohan Subburaman , Poutanen Matti , Ohlsson Claes 
Published: March 2009

Abstract
The stimulatory effects of testosterone (T) on bone can either be through a direct activation of the androgen receptor (AR) or mediated through aromatization of T to estradiol (E2), followed by activation of estrogen receptors (ERs) in bone. Aromatase expression in osteoblasts and reproductive tissues is dependent on different promoters, which are differentially regulated. To study the effect of elevated local aromatization of T to E2 in bone, we developed a transgenic mouse model (Coll-1α1-Arom) that overexpresses the human aromatase gene under the control of the osteoblast specific rat type I α I procollagen promoter. The Coll-1α1-Arom mice expressed human aromatase mRNA specifically in bone and had unaffected serum E2 and T levels. Male Coll-1α1-Arom mice had clearly increased total body BMD, trabecular BMD, cortical BMD, and cortical thickness associated with elevated osteoprotegerin mRNA levels and reduced number of osteoclasts (p &lt; 0.01). Treatment of ovariectomized mice with T increased cortical and trabecular thickness in the Coll-1α1-Arom mice (p &lt; 0.001) but not in the wildtype mice. In conclusion, elevated aromatase expression specifically in osteoblasts results in stimulatory estrogenic effects in bone without increasing serum E2 levels. Because osteoblast-specific aromatase expression results in an increased ER to AR activation ratio in bone, we propose that activation of ERs results in a more pronounced increase in bone mass than what is seen after activation of the AR. Development of osteoblast-specific inducers of aromatase expression might identify substances with stimulatory effects on bone without systemic adverse effects.
Antifracture Efficacy and Reduction of Mortality in Relation to Timing of the First Dose of Zoledronic Acid After Hip Fracture
Authors: Eriksen Erik Fink , Lyles Kenneth W , Colón-Emeric Cathleen S , Pieper Carl F , Magaziner Jay S , Adachi Jonathan D , Hyldstrup Lars , Recknor Chris , Nordsletten Lars , Lavecchia Catherine , Hu Huilin , Boonen Steven , Mesenbrink Peter 
Published: March 2009

Abstract
Annual infusions of zoledronic acid (5 mg) significantly reduced the risk of vertebral, hip, and nonvertebral fractures in a study of postmenopausal women with osteoporosis and significantly reduced clinical fractures and all-cause mortality in another study of women and men who had recently undergone surgical repair of hip fracture. In this analysis, we examined whether timing of the first infusion of zoledronic acid study drug after hip fracture repair influenced the antifracture efficacy and mortality benefit observed in the study. A total of 2127 patients (1065 on active treatment and 1062 on placebo; mean age, 75 yr; 76% women and 24% men) were administered zoledronic acid or placebo within 90 days after surgical repair of an osteoporotic hip fracture and annually thereafter, with a median follow-up time of 1.9 yr. Median time to first dose after the incident hip fracture surgery was ∼6 wk. Posthoc analyses were performed by dividing the study population into 2-wk intervals (calculated from time of first infusion in relation to surgical repair) to examine effects on BMD, fracture, and mortality. Analysis by 2-wk intervals showed a significant total hip BMD response and a consistent reduction of overall clinical fractures and mortality in patients receiving the first dose 2-wk or later after surgical repair. Clinical fracture subgroups (vertebral, nonvertebral, and hip) were also reduced, albeit with more variation and 95% CIs crossing 1 at most time points. We concluded that administration of zoledronic acid to patients suffering a low-trauma hip fracture 2 wk or later after surgical repair increases hip BMD, induces significant reductions in the risk of subsequent clinical vertebral, nonvertebral, and hip fractures, and reduces mortality.
Calcium-Sensing Receptor Expression Is Regulated by Glial Cells Missing-2 in Human Parathyroid Cells
Authors: Mizobuchi Masahide , Ritter Cynthia S , Krits Irina , Slatopolsky Eduardo , Sicard Gregorio , Brown Alex J 
Published: March 2009

Abstract
Glial cells missing-2 (Gcm2) is the key regulating transcription factor for parathyroid gland development. The continued expression of high levels of Gcm2 in mature parathyroid glands suggests that it is required for maintenance of parathyroid cell differentiation. The role of Gcm2 in parathyroid cell physiology, however, has not been fully studied. In this study, we examined the effects of Gcm2 silencing on cultured human parathyroid cells. Collagenase-dispersed human parathyroid cells from patients with chronic kidney disease were placed in monolayer cultures and infected with lentivirus expressing shRNA for human Gcm2. Seventy-two hours after infection, mRNA was processed and analyzed for Gcm2, PTH, vitamin D receptor (VDR), calcium-sensing receptor (CaR), 25-hydroxyvitamin D3 1-α-hydroxylase (1-OHase), and proliferating cell nuclear antigen (PCNA) by real-time PCR (qPCR). Protein expression of affected genes was analyzed by immunoblot 72 h after infection. Gcm2 mRNA and protein were decreased by 74.2 ± 12.2% (SD; n = 3 experiments; p &lt; 0.01) and 67.5 ± 15.7% (n = 2; p &lt; 0.01), respectively. CaR mRNA and protein were reduced by 47.8 ± 21.1% (n = 3; p &lt; 0.01) and 48.1 ± 4.3% (n = 3; p &lt; 0.01), respectively. However, VDR, PTH, 1-OHase, and PCNA were not significantly affected by Gcm2 silencing. Further analysis of CaR mRNA indicated that transcripts containing exon 1B, derived by transcription from CaR promoter 2, were downregulated (58.8 ± 19.27%; n = 3; p &lt; 0.05) by Gcm2 silencing. Exon 1A–containing transcripts from promoter 1 were expressed at very low levels in the cultures. These results indicate that one function of Gcm2 is to maintain high levels of CaR expression in parathyroid cells.
Risedronate in the Treatment of Mild Pediatric Osteogenesis Imperfecta: A Randomized Placebo-Controlled Study
Authors: Rauch Frank , Munns Craig F , Land Christof , Cheung Moira , Glorieux Francis H 
Published: March 2009

Abstract
Intravenous pamidronate is the most widely used treatment for moderate to severe osteogenesis imperfecta (OI). Currently, there is no medical treatment for patients with mild OI. We conducted a single-center randomized double-blind placebo-controlled trial to examine the efficacy and safety of oral risedronate in the treatment of pediatric patients with mild OI. A total of 26 children and adolescents (age, 6.1–17.7 yr; 11 girls) with OI type I were randomized to either placebo (N = 13) or risedronate (N = 13) for 2 yr. Risedronate doses were 15 mg once per week in patients weighing &lt;40 kg and 30 mg once per week in patients weighing &gt;40 kg. After 2 yr of treatment, risedronate decreased serum levels of the bone resorption marker collagen type I N-telopeptide by 35% compared with a 6% reduction with placebo (p = 0.003). Risedronate increased lumbar spine areal BMD Z-scores by 0.65, whereas patients receiving placebo experienced a decrease of 0.15 (p = 0.002). In contrast, no significant treatment differences in bone mass and density were found at the radial metaphysis and diaphysis, the hip, and the total body. Histomorphometric analysis of transiliac bone biopsies at the end of the study period did not show a significant treatment difference in cortical width, trabecular bone volume, or parameters of bone turnover. Similarly, there was no detectable treatment effect on vertebral morphometry, second metacarpal cortical width, grip force, bone pain, or number of new fractures. Regarding safety, risedronate was generally well tolerated, and the incidence of clinical or laboratory adverse experiences was similar among treatment groups. These results suggest that the skeletal effects of oral risedronate are weaker than those that are commonly observed with intravenous pamidronate treatment but still lead to an increase in lumbar spine areal BMD. Future studies should investigate whether oral risedronate is effective in reducing fracture rates in children and adolescents with mild OI type I.
Sequestosome 1 Mutations in Paget's Disease of Bone in Australia: Prevalence, Genotype/Phenotype Correlation, and a Novel Non-UBA Domain Mutation (P364S) Associated With Increased NF-κB Signaling Without Loss of Ubiquitin Binding
Authors: Rea Sarah L , Walsh John P , Ward Lynley , Magno Aaron L , Ward Bryan K , Shaw Barry , Layfield Robert , Kent G Neil , Xu Jiake , Ratajczak Thomas 
Published: March 2009

Abstract
Previously reported Sequestosome 1(SQSTM1)/p62 gene mutations associated with Paget's disease of bone (PDB) cluster in, or cause deletion of, the ubiquitin-associated (UBA) domain. The aims of this study were to examine the prevalence of SQSTM1 mutations in Australian patients, genotype/phenotype correlations and the functional consequences of a novel point mutation (P364S) located upstream of the UBA. Mutation screening of the SQSTM1 gene was conducted on 49 kindreds with PDB. In addition, 194 subjects with apparently sporadic PDB were screened for the common P392L mutation by restriction enzyme digestion. HEK293 cells stably expressing RANK were co-transfected with expression plasmids for SQSTM1 (wildtype or mutant) or empty vector and a NF-κB luciferase reporter gene. GST-SQSTM1 (wildtype and mutant) proteins were used in pull-down assays to compare monoubiquitin-binding ability. We identified SQSTM1 mutations in 12 of 49 families screened (24.5%), comprising 9 families with the P392L mutation and 1 family each with the following mutations: K378X, 390X, and a novel P364S mutation in exon 7, upstream of the UBA. The P392L mutation was found in 9 of 194 (4.6%) patients with sporadic disease. Subjects with SQSTM1 mutations had more extensive disease, but not earlier onset, compared with subjects without mutations. In functional studies, the P364S mutation increased NF-κB activation compared with wildtype SQSTM1 but did not reduce ubiquitin binding. This suggests that increased NF-κB signaling, but not the impairment of ubiquitin binding, may be essential in the pathogenesis of PDB associated with SQSTM1 mutations.
One Year of Transgenic Overexpression of Osteoprotegerin in Rats Suppressed Bone Resorption and Increased Vertebral Bone Volume, Density, and Strength
Authors: Ominsky Michael S , Stolina Marina , Li Xiaodong , Corbin Timothy J , Asuncion Franklin J , Barrero Mauricio , Niu Qing-Tian , Dwyer Denise , Adamu Steven , Warmington Kelly S , Grisanti Mario , Tan Hong L , Ke Hua Z , Simonet William S , Kostenuik Paul J 
Published: March 2009

Abstract
RANKL is an essential mediator of bone resorption, and its activity is inhibited by osteoprotegerin (OPG). Transgenic (Tg) rats were engineered to continuously overexpress OPG to study the effects of continuous long-term RANKL inhibition on bone volume, density, and strength. Lumbar vertebrae, femurs, and blood were obtained from 1-yr-old female OPG-Tg rats (n = 32) and from age-matched wildtype (WT) controls (n = 23). OPG-Tg rats had significantly greater serum OPG (up to 260-fold) and significantly lower serum TRACP5b and osteocalcin compared with WT controls. Vertebral histomorphometry showed significant reductions in osteoclasts and bone turnover parameters in OPG-Tg rats versus WT controls, and these reductions were associated with significantly greater peak load in vertebrae tested through compression. No apparent differences in bone material properties were observed in OPG-Tg rat vertebrae, based on their unchanged intrinsic strength parameters and their normal linear relationship between vertebral bone mass and strength. Femurs from OPG-Tg rats were of normal length but showed mild osteopetrotic changes, including reduced periosteal perimeter (−6%) and an associated reduction in bending strength. Serum OPG levels in WT rats showed no correlations with any measured parameter of bone turnover, mass, or strength, whereas the supraphysiological serum OPG levels in OPG-Tg rats correlated negatively with bone turnover parameters and positively with vertebral bone mass and strength parameters. In summary, low bone turnover after 1 yr of OPG overexpression in rats was associated with increased vertebral bone mass and proportional increases in bone strength, with no evidence for deleterious effects on vertebral material properties.
Evaluation of Pharmaceuticals With a Novel 50-Hour Animal Model of Bone Loss
Authors: Tomimori Yoshiya , Mori Kaoru , Koide Masanori , Nakamichi Yuko , Ninomiya Tadashi , Udagawa Nobuyuki , Yasuda Hisataka 
Published: March 2009

Abstract
Osteoporosis remains a major public health problem through its associated fragility fractures. Several animal models for the study of osteoporotic bone loss, such as ovariectomy (OVX) and denervation, require surgical skills and several weeks to establish. Osteoclast differentiation and activation is mediated by RANKL. Here we report the establishment of a novel and rapid bone loss model by the administration of soluble RANKL (sRANKL) to mice. Mice were injected intraperitoneally with sRANKL and used to evaluate existing anti-osteoporosis drugs. sRANKL decreased BMD within 50 h in a dose-dependent manner. The marked decrease in femoral trabecular BMD shown by pQCT and the 3D images obtained by μCT were indistinguishable from those observed in the OVX model. Histomorphometry showed that osteoclastic activity was significantly increased in the sRANKL-injected mice. In addition, serum biochemical markers of bone turnover such as Ca, C-telopeptide of type 1 collagen (CTX), and TRACP5b were also significantly increased in the sRANKL-injected mice in a dose-dependent manner. Bisphosphonates (BPs), selective estrogen receptor modulators (SERMs), and PTH are commonly used for the treatment of osteoporosis. We successfully evaluated the effects of anti–bone-resorbing agents such as BPs, a SERM, and anti–RANKL-neutralizing antibody on bone resorption in a couple of weeks. We also evaluated the effects of PTH on bone formation in 2 wk. A combination of sRANKL injections and OVX made it possible to evaluate a SERM. The sRANKL model is the simplest, fastest, and easiest of all osteoporosis models and could be useful in the evaluation of drug candidates for osteoporosis.
Introduction of a Phe377del Mutation in ANK Creates a Mouse Model for Craniometaphyseal Dysplasia
Authors: Chen I-Ping , Wang Chiachien J , Strecker Sara , Koczon-Jaremko Boguslawa , Boskey Adele , Reichenberger Ernst J 
Published: March 2009

Abstract
Craniometaphyseal dysplasia (CMD) is a monogenic human disorder characterized by thickening of craniofacial bones and flaring metaphyses of long bones. Mutations for autosomal dominant CMD have been identified in the progressive ankylosis gene ANKH. Previous studies of Ank loss-of-function models, Anknull/null and Ankank/ank mice, suggest that Ank plays a role in the regulation of bone mineralization. However, the mechanism for Ank mutations leading to CMD remains unknown. We generated the first knockin (KI) mouse model for CMD expressing a human mutation (Phe377 deletion) in ANK. Homozygous Ank knockin mice (AnkKI/KI) replicate many typical features of human CMD including hyperostosis of craniofacial bones, massive jawbones, decreased diameters of cranial foramina, obliteration of nasal sinuses, fusion of middle ear bones, and club-shaped femurs. In addition, AnkKI/KI mice have increased serum alkaline phosphatase and TRACP5b, as reported in CMD patients. Biochemical markers of bone formation and bone resorption, N-terminal propeptide of type I procollagen and type I collagen cross-linked C-terminal telopeptide, are significantly increased in AnkKI/KI mice, suggesting increased bone turnover. Interestingly, AnkKI/KI bone marrow–derived macrophage cultures show decreased osteoclastogenesis. Despite the hyperostotic phenotype, bone matrix in AnkKI/KI mice is hypomineralized and less mature, indicating that biomechanical properties of bones may be compromised by the Ank mutation. We believe this new mouse model will facilitate studies of skeletal abnormalities in CMD at cellular and molecular levels.
Activin A Enhances Prostate Cancer Cell Migration Through Activation of Androgen Receptor and Is Overexpressed in Metastatic Prostate Cancer
Authors: Kang Hong-Yo , Huang Hsuan-Ying , Hsieh Chang-Yi , Li Chien-Feng , Shyr Chih-Rong , Tsai Meng-Yin , Chang Chawnshang , Chuang Yao-Chi , Huang Ko-En 
Published: March 2009

Abstract
Bone metastasis is the major cause of mortality associated with prostate cancer. Whereas activin A is known to inhibit prostate cancer cell growth and promote apoptosis, the correlation of elevated activin A with increasing serum prostate-specific antigen (PSA) levels in bone metastatic stages of prostate cancer is well documented. The molecular mechanisms explaining these paradoxical effects of activin A and how activin A influences the progression of prostate cancer with bone metastasis remain unclear. By comparing expression profiles of primary prostate cancer biopsies, with and without bone metastasis, we discovered that the expression of activin A is increased in cases with bone metastatic propensity and correlates with increased androgen receptor (AR), PSA expression, and Gleason scores. Activin A promotes migration of prostate cancer cells to osteoblasts, elevates the AR gene transcription through Smads through binding to AR promoter, and induces nuclear translocation of AR to interact with Smad3. Knockdown of Smad3 by siRNA decreases activin A–promoted AR expression and cancer cell migration. Overexpression of AR reversed Smad3-siRNA suppression on activin A–mediated cell migration to osteoblasts. These data suggest that activation of the AR through Smads is required for activin A–promoted prostate cancer cell migration to bone matrix, thereby promoting the bone metastatic phenotype, and the activin A–Smad–AR axis may be considered a therapeutic target in bone metastatic diseases.
Moderate Ingestion of Alcohol Is Associated With Acute Ethanol-Induced Suppression of Circulating CTX in a PTH-Independent Fashion
Authors: Sripanyakorn Supannee , Jugdaohsingh Ravin , Mander Adrian , Davidson Sarah L , Thompson Richard PH , Powell Jonathan J 
Published: March 2009

Abstract
The “J shape” curve linking the risk of poor bone health to alcohol intake is now well recognized from epidemiological studies. Ethanol and nonethanol components of alcoholic beverages could influence bone remodeling. However, in the absence of a solid underlying mechanism, the positive association between moderate alcoholic intake and BMD remains questionable because of confounding associated social factors. The objective of this work was to characterize the short-term effects of moderate alcohol consumption on circulating bone markers, especially those involved in bone resorption. Two sequential blood-sampling studies were undertaken in fasted healthy volunteers (age, 20–47 yr) over a 6-h period using beer of different alcohol levels (&lt;0.05–4.6%), solutions of ethanol or orthosilicic acid (two major components of beer), and water ± calcium chloride (positive and negative controls, respectively). Study 1 (24 subjects) assessed the effects of the different solutions, whereas study 2 (26 subjects) focused on ethanol/beer dose. Using all data in a “mixed effect model,” we identified the contributions of the individual components of beer, namely ethanol, energy, low-dose calcium, and high-dose orthosilicic acid, on acute bone resorption. Markers of bone formation were unchanged throughout the study for all solutions investigated. In contrast, the bone resorption marker, serum carboxy terminal telopeptide of type I collagen (CTX), was significantly reduced after ingestion of a 0.6 liters of ethanol solution (&gt;2% ethanol; p ≤ 0.01, RM-ANOVA), 0.6 liters of beer (&lt;0.05–4.6% ethanol; p &lt; 0.02), or a solution of calcium (180 mg calcium; p &lt; 0.001), but only after calcium ingestion was the reduction in CTX preceded by a significant fall in serum PTH (p &lt; 0.001). Orthosilicic acid had no acute effect. Similar reductions in CTX, from baseline, were measured in urine after ingestion of the test solutions; however, the biological variability in urine CTX was greater compared with serum CTX. Modeling indicated that the major, acute suppressive effects of moderate beer ingestion (0.6 liters) on CTX were caused by energy intake in the early phase (∼0–3 h) and a “nonenergy” ethanol component in the later phase (∼3 to &gt;6 h). The early effect on bone resorption is well described after the intake of energy, mediated by glucagon-like peptide-2, but the late effect of moderate alcohol ingestion is novel, seems to be ethanol specific, and is mediated in a non–calcitonin- and a non–PTH-dependent fashion, thus providing a mechanism for the positive association between moderate alcohol ingestion and BMD.