bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cadmium Exposure and Distal Forearm Fractures
Authors: Alfvén Tobias , Elinder Carl-Gustaf , Hellström Lennart , Lagarde Frédéric , Järup Lars 
Published: April 2006

Abstract
The aim of this study was to analyze the relationship between low-level cadmium exposure and distal forearm fractures. Altogether, 1021 men and women exposed to cadmium in Sweden were included. The study indicates that cadmium exposure is associated with increased risk of forearm fractures in people over the age of 50.
Introduction: Very few studies have been performed on environmental risk factors for fractures. Cadmium is known to cause damage to the kidneys and in high doses to the bone. The aim of this study was to analyze the relationship between low-level cadmium exposure and distal forearm fractures.
Materials and Methods: A total of 479 men and 542 women, 16-81 years of age, that were environmentally or occupationally exposed to cadmium were examined in 1997. Cadmium in urine was used to estimate dose, and information about previous fractures and risk factors for fractures was obtained from questionnaires. Fractures were validated using medical records. The association between cadmium dose and risk of forearm fracture was evaluated using Cox proportional hazard regression analysis.
Results and Conclusion: The mean urinary cadmium in the study population was 0.74 nmol cadmium/mmol creatinine (10% and 90% percentiles are 0.19 and 1.42, respectively). For fractures occurring after the age of 50 years (n = 558, 32 forearm fractures), the fracture hazard ratio, adjusted for gender and other relevant co-variates, increased by 18% (95% CI, 1.0-38%) per unit urinary cadmium (nmol cadmium/mmol creatinine). When subjects were grouped in exposure categories, the hazard ratio reached 3.5 (90% CI, 1.1, 11) in the group of subjects with urinary cadmium between 2 and 4 nmol/mmol creatinine and 8.8 (90% CI, 2.6, 30) in the group of subjects with ≥4 nmol/mmol creatinine. Associations between cadmium and fracture risk were absent before the age of 50. Cadmium exposure is associated with increased risk of forearm fractures in people over 50 years of age.
Two Novel Mutations at Exon 8 of the Sequestosome 1 (SQSTM1) Gene in an Italian Series of Patients Affected by Paget's Disease of Bone (PDB)
Authors: Falchetti Alberto , Di Stefano Marco , Marini Francesca , Del Monte Francesca , Mavilia Carmelo , Strigoli Debora , De Feo Maria L , Isaia Giovan , Masi Laura , Amedei Antonietta , Cioppi Federica , Ghinoi Valentina , Bongi Susanna Maddali , Di Fede Giuseppina , Sferrazza Carmela , Rini Giovan B , Melchiorre Daniela , Matucci-Cerinic Marco , Brandi Maria L 
Published: April 2006

Abstract
PDB is genetically heterogeneous. Mutations of the sequestosome1 gene have been reported in sporadic and familial forms of Paget's in patients of French Canadian and British descent. Mutational analyses in different ethnic groups are needed to accurately investigate hereditary diseases. We describe two novel mutations of sequestosome1 in 62 Italian sporadic patients, confirming the role of the encoded protein in this disorder.
Introduction: Paget's disease of bone (PDB) is a relatively common disease of bone metabolism reported to affect up to 3% of whites over 55 years of age. The disorder is genetically heterogeneous, and at present, there is scientific evidence that at least eight different human chromosomal loci are correlated with its pathogenesis. Mutations of the sequestosome1 (SQSTM1) gene were identified as responsible for most of the sporadic and familial forms of Paget in patients of French Canadian and British descent. Such mutations were located at exon 7 and 8 levels, encoding for the ubiquitin protein-binding domain (UBA) and representing a mutational hot spot area.
Materials and Methods: To verify the involvement of this gene in Italian subjects affected by PDB, we performed mutational analysis in 62 sporadic PDB cases.
Results: We described three different mutations at exon 8 level: P392L, already described in the French Canadian population and families predominantly of British descendent, and two novel mutations consisting of the amino acid substitutions M404V and G425R. No significant differences in the clinical history of PDB have been observed in patients with SQSTM1 mutations in respect to those without.
Conclusions: Even though our findings suggest a minor involvement of the SQSTM1 gene in the pathogenesis of sporadic Italian Paget's cases, the identification of different significant mutations within the SQSTM1 gene in unrelated, but clinically similar individuals, offers extremely convincing evidence for a causal relationship between this gene and PDB. Longitudinal studies are needed to assess the penetrance of genotype/phenotype correlations. Our findings confirm the evidence of a clustered mutation area at this level in this disorder.
Genetically Modified Animal Models as Tools for Studying Bone and Mineral Metabolism
Authors: Davey Rachel A , MacLean Helen E , McManus Julie F , Findlay David M , Zajac Jeffrey D 
Published: April 2006

Abstract
Genetic modification of mice is a powerful tool for the study of bone development and metabolism. This review discusses the advantages and disadvantages of various approaches used in bone-related research and the contributions these studies have made to bone biology.
Genetic modification of mice is a powerful tool for the study of bone development and metabolism. This review discusses the advantages and disadvantages of various approaches used in bone-related research and the contributions these studies have made to bone biology. The approaches to genetic modification included in this review are (1) overexpression of genes, (2) global gene knockouts, (3) tissue-specific gene deletion, and (4) gene knock-in models. This review also highlights issues that should be considered when using genetically modified animal models, including the rigorous control of genetic background, use of appropriate control lines, and confirmation of tissue specificity of gene expression where appropriate. This technology provides a unique and powerful way to probe the function of genes and is already revolutionizing our approach to understanding the physiology of bone development and metabolism.
Associations Between Baseline Risk Factors and Vertebral Fracture Risk in the Multiple Outcomes of Raloxifene Evaluation (MORE) Study
Authors: Johnell Olof , Kanis John A , Black Dennis M , Balogh Adam , Poor Gyula , Sarkar Somnath , Zhou Chunmei , Pavo Imre 
Published: April 2006

Abstract
Different risk factors may influence the effectiveness of osteoporosis therapies. The interaction of 30 baseline risk factors and the effectiveness of raloxifene in the MORE study were assessed. The efficacy of raloxifene in reducing vertebral fractures is largely independent of the presence of clinical risk factors for osteoporotic fractures.
Introduction: The aim of this analysis was to determine the effect of different risk factors on the effectiveness of raloxifene to reduce vertebral fractures in the Multiple Outcomes of Raloxifene Evaluation (MORE) study using logistic regression models.
Materials and Methods: The association was assessed using univariate analyses and a multivariate model between 30 potential risk factors at baseline and the risk of vertebral fractures after 3 years in the placebo group, as well as the interaction of risk factors with raloxifene therapy (at a dose of 60 or 120 mg/day).
Results and Conclusions: In the univariate analysis of the placebo group, after adjusting for baseline lumbar spine BMD (LS BMD), short stature (odds ratio [OR] = 1.18), age (OR = 1.38), years since menopause (OR = 1.38), impaired cognitive function, visuospatial capabilities (OR = 1.19), impaired musculoskeletal strength (OR = 1.23), low femoral neck BMD (OR = 1.21), and prior vertebral fracture (OR = 4.95) were significantly associated with the incidence of new vertebral fractures. In the univariate analysis, significant interactions were observed between raloxifene treatment and age (p = 0.04), serum triglycerides (p = 0.03), LS BMD (p = 0.08), and diabetes mellitus (p = 0.04). In the multivariate analysis, the effectiveness of raloxifene was independent of almost all risk factors, with the exception of baseline serum triglyceride level and LS BMD, suggesting an increased efficacy of raloxifene in patients with increased triglyceride levels (p = 0.006) and lower LS BMD values (p = 0.008) at baseline. These data suggest that the efficacy of raloxifene in reducing vertebral fractures is largely independent of the presence of clinical risk factors for osteoporotic fractures.
Risk Factors for Incident Vertebral Fractures in Men and Women: The Rotterdam Study
Authors: van der Klift Marjolein , de Laet Chris EDH , McCloskey Eugene V , Johnell Olof , Kanis John A , Hofman Albert , Pols Huibert AP 
Published: April 2006

Abstract
Low BMD and prevalent vertebral fractures are known risk factors for incident vertebral fractures. In 3001 men and women from the Rotterdam Study, prevalent nonvertebral fractures, early menopause, current smoking, and walking aid use were also strong risk factors for incident vertebral fractures.
Introduction: Thus far, age, low BMD, and prevalent vertebral fractures are the only well-known risk factors for incident vertebral fractures. Therefore, our aim was to investigate other potential risk factors for incident vertebral fractures in the elderly.
Materials and Methods: This study was based on the Rotterdam Study, a large prospective population-based cohort study among men and women ≥55 years of age. For 3001 subjects, spinal radiographs were obtained at baseline and again ∼6.3 years later. These follow-up radiographs were scored for vertebral fractures using the McCloskey-Kanis method. Whenever a vertebral fracture was detected, the radiograph was compared with the baseline radiograph. If this fracture was not already present at baseline, it was considered incident. At baseline, information on potential risk factors was obtained.
Results: Low BMD and prevalent vertebral fractures were strong risk factors for incident vertebral fractures in both men and women (RR 2.3 [1.6-3.3] and 2.2 [0.9-5.0] for men and RR 2.1 [1.6-2.6] and 4.1 [2.5-6.7] for women, respectively). For women, age, early menopause (≤45 years of age; RR 1.0 [1.1-3.5]), current smoking (2.1 [1.2-3.5]), and walking aid use (2.5 [1.1-5.5]) were additional independent risk factors. For men, only a history of nonvertebral fractures was a significant independent risk factor (OR 2.4 [1.2-4.8]).
Conclusion: Apart from low BMD and prevalent vertebral fractures, prevalent nonvertebral fractures are associated with an increased incident vertebral fracture risk in men. In women, early menopause, current smoking, and walking aid use are additional independent risk factors for incident vertebral fractures.
Novel UBA Domain Mutations of SQSTM1 in Paget's Disease of Bone: Genotype Phenotype Correlation, Functional Analysis, and Structural Consequences
Authors: Hocking Lynne J , Lucas Gavin JA , Daroszewska Anna , Cundy Tim , Nicholson Geoff C , Donath Judit , Walsh John P , Finlayson Catriona , Cavey James R , Ciani Barbara , Sheppard Paul W , Searle Mark S , Layfield Robert , Ralston Stuart H 
Published: April 2006

Abstract
Three novel missense mutations of SQSTM1 were identified in familial PDB, all affecting the UBA domain. Functional and structural analysis showed that disease severity was related to the type of mutation but was unrelated to the polyubiquitin-binding properties of the mutant UBA domain peptides.
Introduction: Mutations affecting the ubiquitin-associated (UBA) domain of Sequestosome 1 (SQSTM1) gene have recently been identified as a common cause of familial Paget's disease of bone (PDB), but the mechanisms responsible are unclear. We identified three novel SQSTM1 mutations in PDB, conducted functional and structural analyses of all PDB-causing mutations, and studied the relationship between genotype and phenotype.
Materials and Methods: Mutation screening of the SQSTM1 gene was conducted in 70 kindreds with familial PDB. We characterized the effect of the mutations on structure of the UBA domain by protein NMR, studied the effects of the mutant UBA domains on ubiquitin binding, and looked at genotype-phenotype correlations.
Results and Conclusions: Three novel missense mutations affecting the SQSTM1 UBA domain were identified, including a missense mutation at codon 411 (G411S), a missense mutation at codon 404 (M404V), and a missense mutation at codon 425 (G425R). We also identified a deletion leading to a premature stop codon at 394 (L394X). None of the mutations were found in controls. Structural analysis showed that M404V and G425R involved residues on the hydrophobic surface patch implicated in ubiquitin binding, and consistent with this, the G425R and M404V mutants abolished the ability of mutant UBA domains to bind polyubiquitin chains. In contrast, the G411S and P392L mutants bound polyubiquitin chains normally. Genotype-phenotype analysis showed that patients with truncating mutations had more extensive PDB than those with missense mutations (bones involved = 6.05 ± 2.71 versus 3.45 ± 2.46; p &lt; 0.0001). This work confirms the importance of UBA domain mutations of SQSTM1 as a cause of PDB but shows that there is no correlation between the ubiquitin-binding properties of the different mutant UBA domains and disease occurrence or extent. This indicates that the mechanism of action most probably involves an interaction between SQSTM1 and a hitherto unidentified protein that modulates bone turnover.
Association of Five Quantitative Ultrasound Devices and Bone Densitometry With Osteoporotic Vertebral Fractures in a Population-Based Sample: The OPUS Study
Authors: Dr Glüer Claus C , Eastell Richard , Reid David M , Felsenberg Dieter , Roux Christian , Barkmann Reinhard , Timm Wolfram , Blenk Tilo , Armbrecht Gabi , Stewart Alison , Clowes Jackie , Thomasius Friederike E , Kolta Sami 
Published: April 2006

Abstract
We compared the performance of five QUS devices with DXA in a population-based sample of 2837 women. All QUS approaches discriminated women with and without osteoporotic vertebral fractures. QUS of the calcaneus performed as well as central DXA.
Introduction: Quantitative ultrasound (QUS) methods have found widespread use for the assessment of bone status in osteoporosis, but their optimal use remains to be established. To determine QUS performance for current devices in direct comparison with central DXA, we initiated a large population-based investigation, the Osteoporosis and Ultrasound Study (OPUS).
Materials and Methods: A total of 463 women 20–39 years of age and 2374 women 55–79 years of age were measured on five different QUS devices along with DXA of the spine and the proximal femur. Their vertebral fracture status was evaluated radiographically. The association of QUS and DXA with vertebral fracture status was evaluated using logistic regression.
Results: All QUS approaches tested discriminated women with and without osteoporotic vertebral fractures (20% height reduction), with age-adjusted standardized odds ratios ranging 1.2–1.3 for amplitude-dependent speed of sound (AD-SOS) at the finger phalanges, 1.2–1.4 for broadband ultrasound attenuation (BUA) at the calcaneus, and 1.4–1.5 for speed of sound (SOS) at the calcaneus, 1.4–1.6 for DXA of the total femur, and 1.5–1.6 for DXA at the spine. For more severe fractures (40% height reduction), age-adjusted standardized odds ratios increased to up to 1.9 for DXA of the spine and 2.3 for SOS of the calcaneus.
Conclusions: In conclusion, all five QUS devices tested showed significant age-adjusted differences between subjects with and without vertebral fracture. When selecting the strongest variable, QUS of the calcaneus worked as well as central DXA for identification of women at high risk for prevalent osteoporotic vertebral fractures. QUS-based case-finding strategies would allow halving the number of radiographs in high-risk populations, and this strategy works increasingly well for women with more severe vertebral fractures. It is likely that the good performance of QUS was in part achieved by rigorous quality assurance measures that should also be used in clinical practice.
A Single-Dose Placebo-Controlled Study of AMG 162, a Fully Human Monoclonal Antibody to RANKL, in Postmenopausal Women
Authors: Bekker Pirow J , Holloway Donna L , Rasmussen Amy S , Murphy Robyn , Martin Steven W , Leese Philip T , Holmes Gregory B , Dunstan Colin R , DePaoli Alex M 
Published: April 2006

Abstract
The safety and bone antiresorptive effect of a single subcutaneous dose of AMG 162, a human monoclonal antibody to RANKL, was investigated in 49 postmenopausal women. AMG 162 is a potent antiresorptive agent for diseases such as osteoporosis.
Introduction: RANKL is an essential osteoclastic differentiation and activation factor.
Materials and Methods: The bone antiresorptive activity and safety of AMG 162, a fully human monoclonal antibody to RANKL, were evaluated in postmenopausal women in this randomized, double-blind, placebo-controlled, single-dose, dose escalation study. Six cohorts of eight to nine women were randomly assigned to receive a single subcutaneous injection of either AMG 162 or placebo (3:1 ratio). AMG 162 doses were 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg. Subjects were followed up to 6 months in all cohorts and 9 months in the three highest dose cohorts. Second morning void urinary N-telopeptide/creatinine (NTX; Osteomark), serum NTX, and serum bone-specific alkaline phosphatase (BALP, Ostase) were assessed as bone turnover markers.
Results and Conclusions: Forty-nine women were enrolled. A single subcutaneous dose of AMG 162 resulted in a dose-dependent, rapid (within 12 h), profound (up to 84%), and sustained (up to 6 months) decrease in urinary NTX. At 6 months, there was a mean change from baseline of −81% in the 3.0 mg/kg AMG 162 group compared with −10% in the placebo group; serum NTX changes were −56% and 2%, respectively. BALP levels did not decrease remarkably until after 1 month, indicating that the effect of AMG 162 is primarily antiresorptive. Intact parathyroid hormone (PTH) levels increased up to ∼3-fold after 4 days in the 3.0 mg/kg dose group, but returned toward baseline with follow-up. Albumin-adjusted serum calcium did not decrease &gt;10% on average in any group, and no subject had values below 2 mmol/liter. AMG 162 was well tolerated. No related serious adverse events occurred. No clinically meaningful laboratory changes, other than those described above, were observed. In summary, a single subcutaneous dose of AMG 162 resulted in a dose-dependent rapid and sustained decrease from baseline in bone turnover and could be an effective and convenient treatment for osteoporosis.
Effects of Estrogen Replacement Therapy on Bone Turnover in Subchondral Bone and Epiphyseal Metaphyseal Cancellous Bone of Ovariectomized Cynomolgus Monkeys
Authors: Ham Kimberley D , Carlson Cathy S 
Published: April 2006

Abstract
ERT decreases the severity of OA in OVX cynomolgus monkeys. We show that bone formation is greater in subchondral bone compared with epiphyseal/metaphyseal cancellous bone of the proximal tibia in these animals and that ERT decreases bone formation in both sites. ERT may decrease the risk of OA by decreasing bone formation in the SC bone.
Introduction: Estrogen replacement therapy (ERT) decreases the risk of osteoporosis and osteoarthritis (OA) in postmenopausal women and has been shown to have direct effects on cells of the bone and cartilage. The effects of ERT have been studied extensively in cancellous bone, but subchondral (SC) bone directly beneath the articular cartilage has not been specifically evaluated.
Materials and Methods: Adult feral female cynomolgus monkeys were bilaterally ovariectomized (OVX) to simulate menopause; treated with ERT, soy phytoestrogens (SPE), or no hormones (OVX control group) for 3 years; and labeled with calcein before necropsy. At necropsy, the proximal tibias of 20 randomly selected animals from each treatment group were embedded in bioplastic and sectioned. Areas and labels were measured in a carefully defined region of the SC bone and epiphyseal/metaphyseal cancellous (EMC) bone, and derived dynamic and static indices were compared between the SC and EMC bone and among the three treatment groups. Student's t-tests and ANOVA were used to compare the data.
Results and Conclusions: In both the SC and EMC bone, most of the values for the dynamic indices were highest in the OVX control group, intermediate in the SPE group, and lowest in the ERT group. The mineralizing surface, double-labeled surface, and bone formation rate (surface referent) were significantly higher in the SC bone compared with the EMC bone in the OVX control group. The trabecular bone volume was higher in the SPE-treated group compared with the OVX control group. In conclusion, the bone turnover indices were higher in the SC bone compared with the EMC bone, and ERT decreased these indices in both sites. In addition, SPE was protective against loss of bone volume.
Lifestyle Influences on 9-Year Changes in BMD in Young Women
Authors: Mein Anna L , Briffa N Kathryn , Dhaliwal Satvinder S , Price Roger I 
Published: April 2006

Abstract
The effects of dietary calcium intake and physical activity on longitudinal changes in BMD over a mean of 9.4 years were examined in 62 healthy young women. Proximal femur BMD declined, lumbar spine BMD increased, and physical activity was associated with BMD change at intertrochanter and total hip sites.
Introduction: Maximizing premenopausal BMD is an important strategy for the prevention of osteoporosis and resultant fractures later in life.
Materials and Methods: Young women who previously participated in a placebo-controlled 2-year calcium intervention study at a mean age of 18.5 ± 0.3 years were remeasured at 27.8 ± 1.0 years of age. DXA (Hologic QDR 1000W) was used to measure changes in BMD, and lifestyle factors were ascertained by questionnaire.
Results and Conclusions: Early decline in BMD at the neck of femur (−3.3%/decade) and the converse gain in BMD at the lumbar spine (+4.3%/decade) and intertrochanter (+1.9%/decade) suggest site-specific changes in BMD in young premenopausal women. No effect of previous calcium supplementation was seen on current BMD or changes in BMD (p &gt; 0.10). Lifestyle predictors of change in BMD were determined using hierarchical regression analysis after forced correction for the covariates baseline BMD and previous calcium supplementation. Physical activity was positively associated with change in BMD at total hip and intertrochanter sites (β-coefficients, β = 0.26 and 0.26 respectively; p &lt; 0.05). Calcium intake was negatively associated with change in BMD at the lumbar spine (β = −0.27, p &lt; 0.05). Parity was negatively associated with change in BMD at all sites (β = −0.40 to −0.26, p &lt; 0.05). These data show that BMD is already declining at the proximal femur in these healthy young women. Physical activity assists in maintenance of BMD at some sites and thus may contribute to lifelong fracture prevention. There was no positive association between calcium intake and change in BMD.