bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Influence of an Insulin-Like Growth Factor I Gene Promoter Polymorphism on Hip Bone Geometry and the Risk of Nonvertebral Fracture in the Elderly: The Rotterdam Study
Authors: Rivadeneira Fernando , Houwing-Duistermaat Jeanine J , Beck Thomas J , Janssen Joop AMJL , Hofman Albert , Pols Huibert AP , van Duijn Cornelia M , Uitterlinden Andre' G 
Published: April 2006

Abstract
The absence of the wildtype allele of a promoter polymorphism of the IGF-I gene is associated with increased risk (1.5; 95% CI, 1.1-2.0) of fragility fracture in women (n = 4212) but not in men (n = 2799). An approximation of hip bone geometry (from DXA) suggested the polymorphism is associated with bone strength and stability in gender-specific ways.
Introduction: Previously, we found a CA-repeat promoter polymorphism in the insulin-like growth factor I (IGF-I) gene associated with IGF-I levels and BMD in postmenopausal women, but the relationship with fractures is unclear. In this large population-based study of elderly men and women, we examined the association between this IGF-I promoter polymorphism with parameters of bone geometry and the occurrence of fractures.
Material and Methods: Within the Rotterdam Study, a prospective population-based cohort, the IGF-I polymorphism was analyzed in relation to incident nonvertebral fractures in 2799 men and 4212 women followed on average for 8.6 years. Furthermore, we estimated structural parameters of hip bone geometry indirectly from DXA outputs of the femoral neck in 2372 men and 3114 women. We studied neck width, cortical thickness, and the cortical buckling ratio and the section modulus as indexes of bone stability and bending strength.
Results: Women heterozygotes and noncarriers of the allele had, respectively, 1.2 (95% CI, 1.0-1.5) and 1.5 (95% CI, 1.1-2.0) increased risk of having a fragility fracture at older age compared with homozygotes for the 192-bp allele (p trend = 0.0007). In men, fracture risk was not influenced by the polymorphism. Compared with homozygotes for the 192-bp allele, noncarrier males had ∼1% narrower femoral necks and 2.2% lower section moduli (p trend &lt; 0.05). Noncarrier females had 1.7% thinner cortices and 1.6% higher buckling ratios (p trend &lt; 0.05) but no significant differences in femoral neck widths and section moduli. In women with low body mass index, genotype differences in bone strength (section modulus) and fracture risk were accentuated (p interaction = 0.05). The genotype-dependent differences in hip bone geometry did not fully explain the genotype-dependent differences in fracture risk.
Conclusions: The CA-repeat promoter polymorphism in the IGF-I gene is associated with the risk for fragility fracture at old age in women and with bone structure in both genders.
Severe Malignant Osteopetrosis Caused by a GL Gene Mutation
Authors: Quarello Paola , Forni Marco , Barberis Laura , Defilippi Claudio , Campagnoli M Francesca , Silvestro Leandra , Frattini Annalisa , Chalhoub Nader , Vacher Jean , Ramenghi Ugo 
Published: April 2006

Abstract
Infantile malignant autosomal recessive osteopetrosis is a genetically heterogeneous disease caused by the inability of OCLs to resorb and remodel bone, resulting in generalized osteosclerosis and obliteration of marrow spaces and cranial foramina. The classical clinical features are pathological fractures, visual impairment, and bone marrow failure.
Two human genes have been described as the cause of this form of osteopetrosis: the T-cell immune-regulator-1 (TCIRG1) gene, which is mutated in &gt;50% of the patients, and the chloride channel 7 (ClCN7) gene, which accounts for ∼10% of cases. We report the clinical, radiographic, and histopathologic findings of the first human osteopetrosis case caused by a mutation in the grey-lethal (GL) gene. The patient, a 9-day-old male infant, presented with a very severe osteopetrotic phenotype including substantial hepatosplenomegaly since birth, cytopenia, and progressive major liver failure. Skeletal radiographs revealed a generalized increase in bone density with loss of corticomedullary differentiation. Histopathologic bone examination showed the typical osteopetrotic changes, with absence of resorptive activity, and osteoclasts, slightly decreased in number, with evident morphological alterations.
False Positive Rates in Association Studies as a Function of Degree of Stratification
Authors: Koller Daniel L , Peacock Munro , Lai Dongbing , Foroud Tatiana , Econs Michael J 
Published: April 2006

Abstract
To explore the degree to which stratification can cause spurious positive association results, we tested for association between BMD and 373 genetic markers using 381 white and 126 black females. The rate of positive results doubled as the proportion of stratification increased, showing the importance of controlling for stratification in association studies.
Introduction: Population-based association studies are commonly used to test the relationship between polymorphisms in a candidate gene and a disease or trait of interest. Although the collection of samples for this type of study design is relatively cost-effective, the statistical analysis may be susceptible to false positive results because of the effects of population stratification. Such results may occur when the underlying populations differ in both the polymorphism allele frequency and mean trait value.
Materials and Methods: To explore the degree to which stratification can cause spurious positive association results, we analyzed femoral neck BMD data from an unrelated sample of 381 white and 126 black premenopausal females. As part of a previous genome screen, 373 microsatellite markers had been genotyped for each individual. For simplicity of interpretation, each multiallelic marker was reduced to a biallelic marker, with the most common allele as one allele and all other alleles combined as the second allele. As expected, the black women differed substantially for marker allele frequencies and had significantly higher mean femoral neck BMD than their white counterparts. Random subsets of the white and black samples were sampled, with increasing proportions of stratification (0%, 1%, 2%, 5%, 10%, 15%, and 20% black subjects) in the total analyzed sample. ANOVA was used to test for association between the recoded marker and femoral neck BMD.
Results and Conclusions: The rate of positive results for the association test were observed to double as the proportion of stratification increased, with substantial increases in the frequency of false positives even for stratification proportions as small as 2-5%. These results show the importance of controlling for stratification when the trait and the polymorphism allele frequency differ between the races.
Dose-Response Relationships Between Energy Availability and Bone Turnover in Young Exercising Women
Authors: Ihle Rayan , Loucks Anne B 
Published: April 2006

Abstract
To help refine nutritional guidelines for military servicewomen, we assessed bone turnover after manipulating the energy availability of 29 young women. Bone formation was impaired by less severe restrictions than that which increased bone resorption. Military servicewomen and others may need to improve their nutrition to avoid these effects.
Introduction: We determined the dose-response relationship between energy availability (defined as dietary energy intake minus exercise energy expenditure) and selected markers of bone turnover in 29 regularly menstruating, habitually sedentary, young women of normal body composition.
Materials and Methods: For 5 days in the early follicular phase of two menstrual cycles separated by at least 2 months, subjects expended 15 kcal/kgLBM/day in supervised exercise at 70% of aerobic capacity and consumed controlled amounts of a clinical dietary product in balanced (45 kcal/kgLBM/day) and one of three restricted (either 10, 20, or 30 kcal/kgLBM/day) energy availability treatments in random order. Blood was sampled at 10-minute intervals, and urine was collected for 24 h. Samples were assayed for plasma osteocalcin (OC), serum type I procollagen carboxy-terminal propeptide (PICP), and urinary N-telopeptide (NTX).
Results: NTX concentrations (p &lt; 0.01) and indices of bone resorption/formation uncoupling (ZNTX-OC and ZNTX-PICP; both p &lt; 10−4) were increased by the 10 kcal/kgLBM/day treatment. OC and PICP concentrations were suppressed by all restricted energy availability treatments (all p &lt; 0.05). PICP declined linearly (p &lt; 10−6) with energy availability, whereas most of the suppression of OC occurred abruptly between 20 and 30 kcal/kgLBM/day (p &lt; 0.05).
Conclusions: These dose-response relationships closely resembled those of particular reproductive and metabolic hormones found in the same experiment and reported previously: similar relationships were observed for NTX and estradiol; for PICP and insulin; and for OC, triiodothyronine (T3), and insulin-like growth factor (IGF)-I. The uncoupling of bone resorption and formation by severely restricted energy availability, if left to continue, may lead to irreversible reductions in BMD, and the suppression of bone formation by less severe restrictions may prevent young women from achieving their genetic potential for peak bone mass. More prolonged experiments are needed to determine the dose-response relationships between chronic restrictions of energy availability and bone turnover.
Raloxifene Treatment Is Associated With Increased Serum Estradiol and Decreased Bone Remodeling in Healthy Middle-Aged Men With Low Sex Hormone Levels
Authors: Uebelhart Brigitte , Herrmann François , Pavo Imre , Draper Michael W , Rizzoli René 
Published: April 2006

Abstract
In healthy middle-aged men, raloxifene treatment was associated with increased serum estradiol and decreased biochemical markers of bone turnover in subjects with estradiol levels below a threshold of 101.8 pM.
Introduction: We investigated the effects of the selective estrogen receptor modulator raloxifene on bone remodeling in healthy middle-aged men.
Materials and Methods: Forty-three healthy eugonadal men (mean age, 56 years; range, 49-70 years) were enrolled in a randomized placebo-controlled, double-blind, two-sequence crossover study. The subjects received either raloxifene 120 mg/day or placebo for 6 weeks, followed by a 2-month washout period, before crossing over. To predict changes of urinary total deoxypyridinoline/creatinine on raloxifene treatment, we used a logistic regression model to determine cut-off values of sex hormones for highest sensitivity and specificity.
Results: In the whole group, raloxifene treatment was associated with an increase in serum sex hormones, that is, total testosterone (+13%, p &lt; 0.01), bioavailable testosterone (+11%, p = 0.02), total estradiol (+11%, p &lt; 0.002), and bioavailable estradiol (+11%, p = 0.035), and with a decrease in serum osteocalcin (−13%, p &lt; 0.05) and serum total alkaline phosphatase (−6%, p &lt; 0.05). Other biochemical markers of bone turnover remained unchanged. Using a logistic regression model to predict changes in urinary deoxypyridoline, we calculated thresholds for total (101.8 pM) and bioavailable (4.79 pM) estradiol, as well as for total (19.4 nM) and bioavailable (0.35 nM) testosterone. Raloxifene treatment was associated with an increase in serum estradiol and decrease in biochemical markers of bone turnover in men with estradiol values below these estradiol thresholds, without any significant change in subjects with values above them. Similarly, raloxifene treatment was associated with an increase in serum testosterone and a decrease in biochemical markers of bone turnover in those with baseline testosterone values below the testosterone thresholds. The association between antiresorptive effects of raloxifene and low sex hormone levels was more pronounced for estradiol than for testosterone.
Conclusions: The antiresorptive effect of raloxifene was only detectable in men with low baseline estradiol levels. Unlike in postmenopausal women, the increase of estradiol may contribute to the antiresorptive effect of raloxifene in men.
Musculoskeletal Rehabilitation in Osteoporosis: A Review
Authors: Pfeifer Michael , Sinaki Mehrsheed , Geusens Piet , Boonen Steven , Preisinger Elisabeth , Minne Helmut W ,   for the ASBMR Working Group on Musculoskeletal Rehabilitation
Published: April 2006

Abstract
Measures of musculoskeletal rehabilitation play an integral part in the management of patients with increased fracture risk because of osteoporosis or extraskeletal risk factors. This article delineates current scientific evidence concerning nonpharmacologic approaches that are used in conjunction with pharmacotherapy for prevention and management of osteoporosis.
Fractures caused by osteoporotic fragility may be prevented with multidisciplinary intervention programs, including education, environmental modifications, aids, and implementation of individually tailored exercise programs, which are proved to reduce falls and fall-related injuries. In addition, strengthening of the paraspinal muscles may not only maintain BMD but also reduce the risk of vertebral fractures. Given the strong interaction between osteoporosis and falls, selection of patients for prevention of fracture should be based on bone-related factors and on risk factors for falls. Rehabilitation after vertebral fracture includes proprioceptive dynamic posture training, which decreases kyphotic posturing through recruitment of back extensors and thus reduces pain, improves mobility, and leads to a better quality of life. A newly developed orthosis increases back extensor strength and decreases body sway as a risk factor for falls and fall-related fractures. Hip fractures may be prevented by hip protectors, and exercise programs can improve strength and mobility in patients with hip fracture. So far, there is no conclusive evidence that coordinated multidisciplinary inpatient rehabilitation is more effective than conventional hospital care with no rehabilitation professionals involved for older patients with hip fracture. Further studies are needed to evaluate the effect of combined bone- and fall-directed strategies in patients with osteoporosis and an increased propensity to falls.
SRC-1 Is Necessary for Skeletal Responses to Sex Hormones in Both Males and Females
Authors: Yamada Takashi , Kawano Hirotaka , Sekine Keisuke , Matsumoto Takahiro , Fukuda Toru , Azuma Yoshiaki , Itaka Keiji , Chung Ung-il , Chambon Pierre , Nakamura Kozo , Kato Shigeaki , Kawaguchi Hiroshi 
Published: April 2006

Abstract
We created SRC-1−/− mice by mating floxed SRC-1 mice with CMV-Cre transgenic mice. The SRC-1−/− mice showed high turnover osteopenia under physiological conditions and hardly responded to osteoanabolic actions of exogenous androgen and estrogen in males and females, respectively, after gonadectomies, indicating that SRC-1 is essential for the maintenance of bone mass by sex hormones.
Introduction: Steroid receptor coactivator-1 (SRC-1) is the first identified coactivator of nuclear receptors. This study investigated the role of SRC-1 in skeletal tissues of males and females using the deficient (SRC-1−/−) mice.
Materials and Methods: SRC-1 −/− mice were generated by mating our original floxed SRC-1 mice with CMV-Cre transgenic mice. Bone metabolism between 24-week-old SRC-1−/− and wildtype (WT) littermates under physiological conditions was compared in males and females by radiological, histological, and biochemical analyses. Difference of skeletal responses to steroid hormones was examined by gonadectomies and exogenous administration experiments with the hormones. Statistical analysis was performed by ANOVA determined by posthoc testing using Bonferroni's method.
Results and Conclusions: Although SRC-1−/− mice showed no abnormality in growth or major organs, both males and females showed osteopenia with high bone turnover in the trabecular bones, but not in the cortical bones, compared with WT littermates. Their serum levels of sex hormones were upregulated, suggesting a compensatory reaction for the insensitivity to these hormones. Gonadectomies caused decreases in BMDs of SRC-1−/− and WT mice to the same levels; however, replacement with 5α-dihydrotestosterone and 17β-estradiol in males and females, respectively, failed to restore the bone loss in SRC-1−/−, whereas the WT bone volume was increased to the sham-operated levels. In contrast, bone loss by administered prednisolone was similarly seen in SRC-1−/− and WT mice. We conclude that SRC-1 is essential for the maintenance of bone mass by sex hormones, but not for the catabolic action of glucocorticoid, under both physiological and pathological conditions.
Osteocyte Viability and Regulation of Osteoblast Function in a 3D Trabecular Bone Explant Under Dynamic Hydrostatic Pressure
Authors: Takai Erica , Mauck Robert L , Hung Clark T , Guo X Edward 
Published: April 2006

Abstract
A new trabecular bone explant model was used to examine osteocyte-osteoblast interactions under DHP loading. DHP loading enhanced osteocyte viability as well as osteoblast function measured by osteoid formation. However, live osteocytes were necessary for osteoblasts to form osteoids in response to DHP, which directly show osteoblast-osteocyte interactions in this in vitro culture.
Introduction: A trabecular bone explant model was characterized and used to examine the effect of osteocyte and osteoblast interactions and dynamic hydrostatic pressure (DHP) loading on osteocyte viability and osteoblast function in long-term culture.
Materials and Methods: Trabecular bone cores obtained from metacarpals of calves were cleaned of bone marrow and trabecular surface cells and divided into six groups, (1) live cores + dynamic hydrostatic pressure (DHP), (2) live cores + sham, (3) live cores + osteoblast + DHP, (4) live cores + osteoblast + sham, (5) devitalized cores + osteoblast + DHP, and (6) devitalized cores + osteoblast + sham, with four culture durations (2, 8, 15, and 22 days; n = 4/group). Cores from groups 3-6 were seeded with osteoblasts, and cores from groups 5 and 6 were devitalized before seeding. Groups 1, 3, and 5 were subjected to daily DHP loading. Bone histomorphometry was performed to quantify osteocyte viability based on morphology and to assess osteoblast function based on osteoid surface per bone surface (Os/Bs). TUNEL staining was performed to evaluate the mode of osteocyte death under various conditions.
Results: A portion of osteocytes remained viable for the duration of culture. DHP loading significantly enhanced osteocyte viability up to day 8, whereas the presence of seeded osteoblasts significantly decreased osteocyte viability. Cores with live osteocytes showed higher Os/Bs compared with devitalized cores, which reached significant levels over a greater range of time-points when combined with DHP loading. DHP loading did not increase Os/Bs in the absence of live osteocytes. The percentage of apoptotic cells remained the same regardless of treatment or culture duration.
Conclusion: Enhanced osteocyte viability with DHP suggests the necessity of mechanical stimulation for osteocyte survival in vitro. Furthermore, osteocytes play a critical role in the transmission of signals from DHP loading to modulate osteoblast function. This explant culture model may be used for mechanotransduction studies in long-term cultures.
Increase of Both Angiogenesis and Bone Mass in Response to Exercise Depends on VEGF
Authors: Yao Zhenqiang , Lafage-Proust Marie-Hélène , Plouët Jean , Bloomfield Susan , Alexandre Christian , Vico Laurence 
Published: April 2006

Abstract
Physiological angiogenesis during bone remodeling is undefined. Treadmill-running rats displayed bone marrow angiogenesis concomitant with bone formation increase and resorption decrease and upregulation of VEGF and its R1 receptor mRNA in proximal tibia. VEGF blockade over 5 weeks of training fully prevented the exercise-induced bone mass gain.
Introduction: We investigated the role of vascular endothelial growth factor (VEGF) and angiogenesis in the osteogenic response to exercise.
Materials and Methods: Nine-week-old male Wistar rats were treadmill-trained at 60% VO2max for various periods. Bone and vascular histomorphometry was performed after 2- and 5-week experiments. On-line RT PCR for VEGF and its receptors R1 and R2 was done after a 10-day experiment. In the 5-week experiment, running rats received either a VEGF inhibitory antibody or a placebo.
Results: After 2 weeks, tibial BMD did not change; however, vessel number in the proximal metaphysis increased by 20% in running versus sedentary rats. In running rats, vessel number correlated positively (r = 0.88) with bone formation rate and negatively (r = −0.85) with active resorption surfaces. After 10 days of training, upregulation of VEGF and VEGF receptor R1 mRNA was detected in periosteum and metaphyseal bone. VEGF blockade in 5-week trained rats fully prevented the exercise-induced increase in metaphyseal BMD (9%) and cancellous bone volume (BV/TV; 25%), as well as the increased vessel number (25%). In 5-week placebo-treated running rats, bone formation rate returned to initial values, whereas osteoclastic surfaces continued to decline compared with both sedentary and anti-VEGF-treated running rats.
Conclusion: VEGF signaling-mediated bone angiogenesis is tightly related to exercise-induced bone cellular uncoupling and is indispensable for bone gain induced by exercise.
Aged Mice Require Full Transcription Factor, Runx2/Cbfa1, Gene Dosage for Cancellous Bone Regeneration After Bone Marrow Ablation
Authors: Tsuji Kunikazu , Komori Toshihisa , Noda Masaki 
Published: April 2006

Abstract
Runx2 is prerequisite for the osteoblastic differentiation in vivo. To elucidate Runx2 gene functions in adult bone metabolism, we conducted bone marrow ablation in Runx2 heterozygous knockout mice and found that aged (but not young) adult Runx2 heterozygous knockout mice have reduced new bone formation capacity after bone marrow ablation. We also found that bone marrow cells from aged Runx2 heterozygous knockout mice have reduced ALP+ colony-forming potential in vitro. This indicates that full Runx2 dosage is needed for the maintenance of osteoblastic activity in adult mice.
Introduction: Null mutation of the Runx2 gene results in total loss of osteoblast differentiation, and heterozygous Runx2 deficiency causes cleidocranial dysplasia in humans and mice. However, Runx2 gene functions in adult bone metabolism are not known. We therefore examined the effects of Runx2 gene function in adult mice with heterozygous loss of the Runx2 gene.
Materials and Methods: Bone marrow ablation was conducted in young adult (2.5 ± 0.5 months old) or aged adult (7.5 ± 0.5 months old) Runx2 heterozygous knockout mice and wildtype (WT) littermates. Cancellous bone regeneration was evaluated by 2D μCT.
Results: Although new bone formation was observed after bone marrow ablation in the operated bone marrow cavity of WT mice, such bone formation was significantly reduced in Runx2 heterozygous knockout mice. Interestingly, this effect was observed specifically in aged but not young adult mice. Runx2 heterozygous deficiency in aged mice significantly reduced the number of alkaline phosphatase (ALP)+ cell colonies in the bone marrow cell cultures, indicating a reduction in the numbers of osteoprogenitor cells. Such effects of heterozygous Runx2 deficiency on osteoblasts in vitro was specific to the cells from aged adult mice, and it was not observed in the cultures of marrow cells from young adult mice.
Conclusion: These results indicate that full gene dosage of Runx2 is required for cancellous bone formation after bone marrow ablation in adult mice.