bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Intravenous Pamidronate Treatment in Infants With Osteogenesis Imperfecta: Clinical and Histomorphometric Outcome
Authors: Munns Craig FJ , Rauch Frank , Travers Rose , Glorieux Francis H 
Published: April 2006

Abstract
Clinical and histomorphometric outcome was compared between children with OI who had received pamidronate since infancy and age-matched patients who had never received pamidronate. Pamidronate was associated with improved vertebral shape and mass, higher cortical width, increased cancellous bone volume, and suppressed bone turnover.
Introduction: Observations in small patient series indicate that infants with severe osteogenesis imperfecta (OI) benefit from treatment with cyclical intravenous pamidronate. However, detailed analyses of outcome are lacking for this age group.
Materials and Methods: Clinical outcome was evaluated in 29 children with OI types I (n = 3), III (n = 14), or IV (n = 12) who started pamidronate therapy before 2 years of age (age at treatment onset: median, 6 months; range, 2 weeks to 23 months) and who had completed 3 years of treatment (total annual pamidronate dose, 9 mg/kg). They were compared with a historical control group of 29 untreated children with severe OI who were matched for OI type and age at the 3-year treatment time-point. In addition, iliac bone histomorphometry was compared between 24 pamidronate-treated patients and 24 age-matched OI patients who had not received pamidronate.
Results: Morphometric evaluation of lumbar vertebrae (L1-L4) showed that the shape of vertebral bodies was better preserved in pamidronate-treated patients. This was accompanied by significantly higher lumbar spine areal and volumetric BMD (+110 and +96%, respectively) and a larger vertebral bone volume (+26%) on densitometry. Regarding mobility function, the Pediatric Evaluation of Disability Inventory gross motor score was 50% greater in the pamidronate group (p &lt; 0.001). Iliac bone histomorphometry showed 61% higher cortical width and 89% higher cancellous bone volume in pamidronate-treated patients. Bone formation rate per bone surface in the pamidronate group was only 17% that of untreated patients.
Conclusions: In conclusion, this study suggests that cyclical pamidronate treatment started in infancy leads to improved bone strength and better gross motor function but also suppresses bone turnover markedly. It is therefore prudent to reserve pamidronate treatment to infant OI patients who present with a moderate to severe phenotype.
Examining Bone Surfaces Across Puberty: A 20-Month pQCT Trial
Authors: Kontulainen Saija A , Macdonald Heather M , Khan Karim M , McKay Heather A 
Published: April 2006

Abstract
This follow-up study assessed sex differences in cortical bone growth at the tibial midshaft across puberty. In both sexes, periosteal apposition dominated over endosteal resorption. Boys had a greater magnitude of change at both surfaces, and thus, a greater increase in bone size across puberty. Relative increase in cortical bone area was similar between sexes.
Introduction: Generally, sex differences in bone size become most evident as puberty progresses. This was thought to be caused, in part, by greater periosteal apposition in boys, whereas endosteal apposition prevailed in girls. However, this premise is based on evidence from cross-sectional studies and planar measurement techniques. Thus, our aim was to prospectively evaluate sex-specific changes in cortical bone area across puberty.
Materials and Methods: We used pQCT to assess the tibial midshaft (50% site) at baseline and final (20 months) in girls (N = 68) and boys (N = 60) across early-, peri-, and postpuberty. We report total bone cross-sectional area (ToA, mm2), cortical area (CoA, mm2), marrow cavity area (CavA, mm2), and CoA/ToA ratio.
Results: Children were a mean age of 11.9 ± 0.6 (SD) years at baseline. At the tibia, CoA ranged from 230 ± 44, 261 ± 50, and 258 ± 46 in early-, peri-, and postpubertal girls. In boys, comparable values were 223 ± 36 (early), 264 ± 38 (peri), and 281 ± 77 (postpubertal). There was no sex difference for ToA or CoA at baseline. Increase in ToA and CoA was, on average, 10% greater for boys than girls across maturity groups. The area of the marrow cavity increased in all groups, but with considerable variability. The increase in CavA was significantly less for girls than boys in the early- and postpubertal groups. Change in CoA/ToA was similar between sexes across puberty.
Conclusion: Both sexes showed a similar pattern of change in CoA at the tibial midshaft, where periosteal apposition dominated over endosteal resorption. Boys showed a greater magnitude of change at both surfaces, and thus, showed a greater increase in bone size across puberty. The relative increase in cortical area was similar between sexes. These pQCT findings provide no evidence for endosteal apposition in postmenarchal girls.
α-Lipoic Acid Inhibits TNF-α-Induced Apoptosis in Human Bone Marrow Stromal Cells
Authors: Byun Chang-Hyun , Koh Jung-Min , Kim Dong Kwan , Park Seung-Il , Lee Ki-Up , Kim Ghi Su 
Published: April 2006

Abstract
TNF-α is an important mediator of bone loss. In the HS-5 hBMSC, TNF-α and H2O2 increased intracellular ROS levels and induced cell apoptosis through activation of caspases, JNK and NF-κB. α-Lipoic acid prevented these changes induced by TNF-α and H2O2, suggesting its potential therapeutic applications in attenuating bone loss.
Introduction: Oxidative stress is an important mediator of bone loss. TNF-α, which plays a critical role in the bone loss after menopause, has been shown to increase intracellular oxidative stress. Because oxidative stress is associated with cell death, we analyzed the apoptotic effects of TNF-α and H2O2 on human bone marrow stromal cells (hBMSCs). We also examined the protective effects of an important biological thiol antioxidant, α-lipoic acid (α-LA), against TNF-α- and H2O2-induced apoptosis.
Materials and Methods: Using the HS-5 hBMSC cell line, we tested whether TNF-α-induced apoptosis was mediated by the generation of excessive reactive oxygen species (ROS). Apoptosis was determined by 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay, trypan blue exclusion assay, quantitation of histone-associated DNA fragments in cytosol, and the activation of caspases. The mechanisms mediating these apoptotic effects were determined by Western blotting and enzyme immunoassay.
Results: Both TNF-α and H2O2 increased intracellular ROS levels, reduced total cellular glutathione levels, activated caspases-3, -9, and -8, and enhanced hBMSC apoptosis. The activation of c-jun N-terminal kinase (JNK) and NF-κB mediated these apoptotic effects. Pretreatment of cells with α-LA prevented these changes induced by TNF-α and H2O2.
Conclusions: Our data show that TNF-α increases intracellular ROS in hBMSC and that TNF-α and H2O2 induce apoptosis in hBMSC through the activation of JNK and NF-κB. Our findings also suggest that α-LA may have therapeutic applications in halting or attenuating bone loss associated with increased oxidative stress.
An Autosomal Dominant High Bone Mass Phenotype in Association With Craniosynostosis in an Extended Family Is Caused by an LRP5 Missense Mutation
Authors: Kwee Mei Lan , Balemans Wendy , Cleiren Erna , Gille Johan JP , Van Der Blij Frits , Sepers Jan M , Van Hul Wim 
Published: April 2006

Abstract
Gain-of-function mutations in LRP5 have been shown to cause high BMD disorders showing variable expression of some clinical symptoms, including torus palatinus and neurological complications. In an extended family, we were able to add craniosynostosis and developmental delay to the clinical spectrum associated with LRP5 mutations.
We report on an extended four-generation family with 13 affected individuals (7 men and 6 women) in which an autosomal dominant type of osteosclerosis segregates. Osteosclerosis was most pronounced in the cranial base and calvarium, starting in early childhood with variable expression and a progressive character. Craniosynostosis at an early age was reported in four affected family members (two males and two females). The patients also presented with dysmorphic features (macrocephaly, brachycephaly, wide and high forehead, hypertelorism, prominent cheekbones, prominent jaw). They have normal height and proportions. Neurological complications like entrapment of cranial nerves resulting in optical nerve atrophy, hearing loss, and facial palsy were reported in two individuals. A mild developmental delay was reported in three affected individuals. None of the patients have torus palatinus, increased rate of fractures, osteomyelitis, hepatosplenomegaly, or pancytopenia. A missense mutation 640G→A (A214T) in the low-density lipoprotein receptor-related protein 5 (LRP5) gene was found in all affected individuals analyzed, including cases in whom craniosynostosis, a mild developmental delay, and/or macrocephaly is observed. To our knowledge, this is the first report in the literature of patients presenting with autosomal dominant osteosclerosis in whom a variable expression of craniosynostosis, macrocephaly, and mild developmental delay is observed, which is most likely associated with a mutation in the LRP5 gene. These phenotypes can therefore be added to the clinical spectrum of LRP5-associated bone disorders.
Predictive Value of BMD for Hip and Other Fractures
Authors: Johnell Olof , Kanis John A , Oden Anders , Johansson Helena , De Laet Chris , Delmas Pierre , Eisman John A , Fujiwara Seiko , Kroger Heikki , Mellstrom Dan , Meunier Pierre J , Melton L Joseph , O'Neill Terry , Pols Huibert , Reeve Jonathan , Silman Alan , Tenenhouse Alan 
Published: April 2006

Abstract
The relationship between BMD and fracture risk was estimated in a meta-analysis of data from 12 cohort studies of ∼39,000 men and women. Low hip BMD was an important predictor of fracture risk. The prediction of hip fracture with hip BMD also depended on age and z score.
Introduction: The aim of this study was to quantify the relationship between BMD and fracture risk and examine the effect of age, sex, time since measurement, and initial BMD value.
Materials and Methods: We studied 9891 men and 29,082 women from 12 cohorts comprising EVOS/EPOS, EPIDOS, OFELY, CaMos, Rochester, Sheffield, Rotterdam, Kuopio, DOES, Hiroshima, and 2 cohorts from Gothenburg. Cohorts were followed for up to 16.3 years and a total of 168,366 person-years. The effect of BMD on fracture risk was examined using a Poisson model in each cohort and each sex separately. Results of the different studies were then merged using weighted coefficients.
Results: BMD measurement at the femoral neck with DXA was a strong predictor of hip fractures both in men and women with a similar predictive ability. At the age of 65 years, risk ratio increased by 2.94 (95% CI = 2.02-4.27) in men and by 2.88 (95% CI = 2.31-3.59) in women for each SD decrease in BMD. However, the effect was dependent on age, with a significantly higher gradient of risk at age 50 years than at age 80 years. Although the gradient of hip fracture risk decreased with age, the absolute risk still rose markedly with age. For any fracture and for any osteoporotic fracture, the gradient of risk was lower than for hip fractures. At the age of 65 years, the risk of osteoporotic fractures increased in men by 1.41 per SD decrease in BMD (95% CI = 1.33-1.51) and in women by 1.38 per SD (95% CI = 1.28-1.48). In contrast with hip fracture risk, the gradient of risk increased with age. For the prediction of any osteoporotic fracture (and any fracture), there was a higher gradient of risk the lower the BMD. At a z score of -4 SD, the risk gradient was 2.10 per SD (95% CI = 1.63-2.71) and at a z score of -1 SD, the risk was 1.73 per SD (95% CI = 1.59-1.89) in men and women combined. A similar but less pronounced and nonsignificant effect was observed for hip fractures. Data for ultrasound and peripheral measurements were available from three cohorts. The predictive ability of these devices was somewhat less than that of DXA measurements at the femoral neck by age, sex, and BMD value.
Conclusions: We conclude that BMD is a risk factor for fracture of substantial importance and is similar in both sexes. Its validation on an international basis permits its use in case finding strategies. Its use should, however, take account of the variations in predictive value with age and BMD.
Fibrodysplasia Ossificans Progressiva (FOP), a Disorder of Ectopic Osteogenesis, Misregulates Cell Surface Expression and Trafficking of BMPRIA
Authors: de la Peña Lourdes Serrano , Billings Paul C , Fiori Jennifer L , Ahn Jaimo , Kaplan Frederick S , Shore Eileen M 
Published: April 2006

Abstract
FOP is a disorder in which skeletal muscle is progressively replaced with bone. FOP lymphocytes, a model system for exploring the BMP pathway in these patients, exhibit a defect in BMPRIA internalization and increased activation of downstream signaling, suggesting that altered BMP receptor trafficking underlies ectopic bone formation in this disease.
Introduction: Fibrodysplasia ossificans progressiva (FOP) is a severely disabling disorder characterized by progressive heterotopic ossification of connective tissues. Whereas the genetic defect and pathophysiology of this condition remain enigmatic, BMP4 mRNA and protein are overexpressed, and mRNAs for a subset of secreted BMP antagonists are not synthesized at appropriate levels in cultured lymphocytes from FOP patients. These data suggest involvement of altered BMP signaling in the disease. In this study, we investigate whether the abnormality is associated with defective BMP receptor function in lymphocytes.
Materials and Methods: Cell surface proteins were quantified by fluorescence-activated cell sorting (FACS). Protein phosphorylation was assayed by immunoprecipitation and immunoblotting. Protein synthesis and degradation were examined by [35S]methionine labeling and pulse-chase assays. mRNA was detected by RT-PCR.
Results: FOP lymphocytes expressed 6-fold higher levels of BMP receptor type IA (BMPRIA) on the cell surface compared with control cells and displayed a marked reduction in ligand-stimulated internalization and degradation of BMPRIA. Moreover, in control cells, BMP4 treatment increased BMPRIA phosphorylation, whereas BMPRIA showed ligand-insensitive constitutive phosphorylation in FOP cells. Our data additionally support that the p38 mitogen-activated protein kinase (MAPK) signaling pathway is a major BMP signaling pathway in these cell lines and that expression of inhibitor of DNA binding and differentiation 1 (ID-1), a transcriptional target of BMP signaling, is enhanced in FOP cells.
Conclusions: These data extend our previous observations of misregulated BMP4 signaling in FOP lymphocytes and show that cell surface overabundance and constitutive phosphorylation of BMPRIA are associated with a defect in receptor internalization. Altered BMP receptor trafficking may play a significant role in FOP pathogenesis.
Age of Attainment of Peak Bone Mass Is Site Specific in Swedish Men—The GOOD Study
Authors: Lorentzon Mattias , Mellström Dan , Ohlsson Claes 
Published: April 2006

AbstractResults from this study suggest that PBM has been attained in the spine and femoral neck, but not in the radius or tibia, in 18- to 20-year-old men, in which an endosteal contraction and increase in cortical volumetric BMD is observed.Introduction: Peak bone mass (PBM) is an important determinant for the risk of osteoporosis. In men, the age of attainment of PBM has been under some controversy. The objective of this study was to determine if peak bone mass had been attained, and whether it is site specific, in 18- to 20-year-old Swedish men.Materials and Methods: The Gothenburg Osteoporosis and Obesity Determinants (GOOD) Study consists of 1068 men, 18.9 ± 0.6 years of age. BMD was measured using both DXA and pQCT. Environmental factors, such as dietary intake and physical activity, were assessed through questionnaires. The independent predictors of BMD were assessed through multiple linear regression, including age, height, weight, calcium intake, smoking, and physical activity.Results and Conclusions: We show, in a large well-characterized cohort, that age was not an independent predictor of BMD of the lumbar spine, femoral neck, or total body, indicating that peak BMD has been achieved in these skeletal sites, whereas it was an independent predictor of BMD of the radius, suggesting that peak BMD has not yet been attained in the long bones. pQCT analyses of the radius and the tibia revealed that age was associated with cortical volumetric BMD and endosteal contraction of the radius and tibia. These results show that the age of attainment of PBM is site specific.
Ras-Association Domain Family 1 Protein, RASSF1C, Is an IGFBP-5 Binding Partner and a Potential Regulator of Osteoblast Cell Proliferation
Authors: Amaar Yousef G , Baylink David J , Mohan Subburaman 
Published: April 2006

Abstract
The goal of this study was to identify downstream signaling molecules involved in mediating the IGF-independent effects of IGFBP-5 in osteoblasts. We identified RASSF1C, a member of the RASSF1 gene products, as a IGFBP-5 binding partner and as a potential mediator of IGFBP-5 effects on ERK phosphorylation and cell proliferation.
Introduction: It has been predicted that the intrinsic growth factor action of insulin-like growth factor binding protein (IGFBP)-5 involves either the binding of IGFBP-5 to a putative receptor to induce downstream signaling pathways and/or intracellular translocation of IGFBP-5 to bind to potential signaling molecules involved in osteoblast cell regulation. This study reports the characterization of isoform C of the Ras association family 1 (RASSF1C) gene as an interacting partner of IGFBP-5.
Materials and Methods: IGFBP-5 was used as bait in a yeast two-hybrid screen of a human osteosarcoma cDNA library. Expression levels of RASSF1C were measured by RT-PCR and/or Northern blot. IGFBP-5 effects on ERK phosphorylation were evaluated by immunoblot analysis. The effect of RASSF1C siRNA on cell proliferation was measured by the AlamarBlue assay.
Results: One of the clones that interacted strongly with the bait under high stringency conditions corresponded to RASSF1C. The interaction between RASSF1C and IGFBP-5 was confirmed by in vitro co-immunoprecipitation studies. Northern blot and RT-PCR analysis showed that RASSF1C was expressed in a variety of osteoblast cell types that produce IGFBP-5. Addition of synthetic RASSF1C-specific small interfering (si) RNA duplex or use of a RASSF1C-specific si-hairpin plasmid caused a decrease in cell number and abolished IGFBP-5-induced extracellular signal-regulated kinase (ERK)-1/2 phosphorylation but had no effect on IGFBP-5-induced increases in alkaline phosphatase (ALP) activity.
Conclusions: We have shown a novel interaction between IGFBP-5 and RASSF1C. Our findings that silencing of RASSF1C results in the reduction of osteoblast cell proliferation and that IGFBP-5 treatment increases phosphorylation of ERK-1/2 raise the possibility that RASSF1C, a Ras effector, could, in part, contribute to mediating the effects of IGFBP-5 on ERK phosphorylation and, consequently, cell proliferation.
Intravenous Bisphosphonate Therapy Increases Radial Width in Adults With Osteogenesis Imperfecta
Authors: Gatti Davide , Viapiana Ombretta , Lippolis Irma , Braga Vania , Prizzi Rosangela , Rossini Maurizio , Adami Silvano 
Published: April 2006

Abstract
Neridronate therapy in adult patients with OI significantly increases the cross-sectional area of the proximal radius. This observation may provide an additional explanation for the antifracture efficacy of bisphosphonates.
Introduction: Bisphosphonate therapy decreases by 70-90% the fracture risk in patients with osteogenesis imperfecta (OI). This decrease is somewhat greater than that expected from the BMD changes, supporting the hypothesis that bisphosphonate therapy is associated with structural changes, not detectable by BMD measurements.
Materials and Methods: To explore this hypothesis, pQCT measurements at the nondominant radius were obtained in a group of adult OI patients participating in a randomized clinical trial with neridronate.
Results: The total volumetric BMD of the ultradistal radius rose significantly in patients treated with neridronate and calcium + vitamin D (neridronate group) compared with patients treated with calcium + vitamin D alone (control group). No significant differences were observed in trabecular BMD and in volumetric cortical density in either group. In the neridronate group, the cross-sectional area rose significantly versus both baseline values and the control group. These latter changes were associated with ∼20% increases in bending breaking resistance index (BBRI).
Conclusion: Our observation, if extended to postmenopausal osteoporosis, may provide a new explanation for the fracture risk reduction observed in osteoporotic patients treated with bisphosphonates.
An In Vivo Model to Study Osteogenic Gene Regulation: Targeting an Avian Retroviral Receptor (TVA) to Bone With the Bone Sialoprotein (BSP) Promoter
Authors: Li Ling , Zhu JI , Tu Qisheng , Yamauchi Masato , Sodek Jaro , Karsenty Gerard , Tang Jean , Chen Jake 
Published: April 2006

Abstract
To study bone development in vivo, a transgenic mouse model was established in which an avian retroviral receptor (TVA) gene driven by the BSP promoter was selectively expressed in skeletal tissues. The model was validated by showing suppressed BSP expression and delayed bone and tooth formation after infection with a virus expressing a mutated Cbfa1/Runx2 gene.
Introduction: Tissue-specific expression of the avian retroviral (TVA) receptor can be used to efficiently target ectopic expression of genes in vivo. To determine the use of this approach for studies of osteogenic differentiation and bone formation at specific developmental stages, transgenic mice expressing the TVA receptor under the control of a 5-kb bone sialoprotein (BSP) promoter were generated. The mice were first analyzed for tissue-specific expression of the TVA gene and then, after infection with a viral construct, for the effects of a dominant-negative form of the Cbfa1/Runx2 transcription factor on bone formation.
Materials and Methods: We first generated transgenic mice (BSP/TVA) in which the TVA gene was expressed under the control of a 4.9-kb mouse BSP promoter. The tissue-specific expression of the TVA gene was analyzed by RT-PCR, in situ hybridization, and immunohistochemistry and compared with the expression of the endogenous BSP gene. A 396-bp fragment of mutated Cbfa1/Runx2 (Cbfa1mu) encoding the DNA-binding domain was cloned into a RCASBP (A) viral vector, which was used to infect neonatal BSP/TVA mice.
Results and Conclusion: Expression of the TVA receptor mRNA and protein in the transgenic mice was consistent with the expression of endogenous BSP. Four days after systemic infection with the Cbfa1mu-RCASBP (A) vector, RT-PCR analyses revealed that the expression of BSP mRNA in tibia and mandibles was virtually abolished, whereas a 30% reduction was seen in calvarial bone. After 9 days, BSP expression in the tibia and mandible was reduced by 45% in comparison with control animals infected with an empty RCASBP vector, whereas BSP expression in the membranous bone of calvariae was decreased ∼15%. However, after 4 and 8 weeks, there was almost no change in BSP expression in any of the bone tissues. In comparison, a reduction in osteopontin expression was only observed 9 days after viral transfection in the three bones. Histomorphological examination revealed that bone formation and tooth development were delayed in some of the mice infected with mutated Cbfa1. These studies show that BSP/TVA transgenic mice can be used to target genes to sites of osteogenesis, providing a unique system for studying molecular events associated with bone formation in vivo.