bluuebunny/crossref_metadata_2025_split huggingface dataset:
Umbilical Venous IGF-1 Concentration, Neonatal Bone Mass, and Body Composition
Authors: Javaid MK , Godfrey KM , Taylor P , Shore SR , Breier B , Arden NK , Cooper C 
Published: April 2006

AbstractIGF-1 is a key growth factor during fetal life. Using DXA, we found that the concentration of IGF-1 in umbilical cord serum is strongly related to neonatal whole body bone mineral content, lean mass, and fat mass. However IGF-1 did not explain the relationships of maternal smoking, fat mass, and physical activity with neonatal bone mass. The study supports a direct role for circulating IGF-1 in growth of the fetal skeleton.Introduction: Evidence is accumulating that the risk of osteoporosis in later life may be determined in part by environmental influences during intrauterine and early postnatal life. We previously reported that maternal birthweight, smoking, fat stores, and physical activity during pregnancy predict neonatal bone mass. While the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis is an important determinant of postnatal skeletal growth, there are few data relating the concentration of growth factors in umbilical cord blood to bone mineral content (BMC) and other indices of body composition in the newborn infant.Materials and Methods: We conducted a population-based study in a cohort of full-term, newborn infants whose mothers were characterized for lifestyle, body composition, and nutrition through their normal pregnancies. In a sample of 119 infants from the cohort, we related cord serum IGF-1 and insulin-like growth factor binding protein (IGFBP)-3 concentrations to neonatal body composition measured by DXA and evaluated the extent to which this cytokine mediates the previously reported effects of maternal diet and lifestyle on neonatal bone mass.Results: There were strong positive associations between cord serum IGF-1 concentration and whole body BMC (r = 0.38, p &lt; 0.001), whole body lean mass (r = 0.40, p &lt; 0.001), and whole body fat mass (r = 0.50, p &lt; 0.001) after adjusting for gestational age and sex. There was no association between cord serum IGF-1 and BMC adjusted for bone size. Neither cord serum IGF-1 nor IGFBP-3 explained the relationships that we previously reported between maternal influences and neonatal bone mass.Conclusions: Cord serum IGF-1 is more closely related to the size of the neonatal skeleton than to its degree of mineralization. Documented maternal determinants of neonatal bone mass seem to mediate their effects independently of variations in cord serum IGF-1 in healthy pregnancies.
Vignettes in Osteoporosis: A Road Map to Successful Therapeutics
Authors: Rosen Clifford J , Black Dennis M , Greenspan Susan L 
Published: April 2006

Abstract
The diagnosis and management of osteoporosis have become increasingly more complex as new drugs enter the marketplace and meta-analyses of randomized trials with “other” agents become more prolific. We describe five common clinical scenarios encountered in the practice of osteoporosis medicine and various road maps that could lead to successful therapy.
Introduction: The diagnosis and treatment of osteoporosis have changed dramatically in the last decade. Advances in diagnostic technologies and a range of newer treatment options have provided the clinician with a wide array of choices for treating this chronic disease. Despite the issuance of several “guidelines” and practice recommendations, there still remains confusion among clinicians about basic approaches to the management of osteoporosis. This paper should be used as a case-based approach to define optimal therapeutic choices.
Materials and Methods: Five representative cases were selected from two very large clinical practices (Bangor, ME; Pittsburgh, PA). Diagnostic modalities and treatment options used in these cases were selected on an evidence-based analysis of respective clinical trials. Subsequent to narrative choices by two metabolic bone disease specialists (SG and CR), calculation of future fracture risk and selection of potential alternative therapeutic regimens were reviewed and critiqued by an epidemiologist (DB).
Results: A narrative about each case and possible management choices for each of the five cases are presented with references to justify selection of the various therapeutic options. Alternatives are considered and discussed based on literature and references through July 2003. The disposition of the individual patient is noted at the end of each case.
Conclusions: A case-based approach to the management of osteoporosis provides a useful interface between guidelines, evidence-based meta-analyses, and clinical practice dilemmas.
Adipogenic Differentiation of Human Adult Stem Cells From Bone Marrow Stroma (MSCs)
Authors: Sekiya Ichiro , Larson Benjamin L , Vuoristo Jussi T , Cui Jian-Guo , Prockop Darwin J 
Published: April 2006

Abstract
We assayed gene expressions during adipogenesis of human MSCs. Microarray assays demonstrated time-dependent increases in expression of 67 genes, including 2 genes for transcription factors that were not previously shown to be expressed during adipogenesis.
Introduction: Increased numbers of bone marrow adipocytes have been observed in patients with osteoporosis and aplastic anemia, but the pathological mechanisms remain unknown. Recently, microarray assays for mRNAs were used to follow adipogenic differentiation of the preadipocytic cell line, 3T3-L1, but adipogenic differentiation has not been examined in primary cells from bone marrow. Here we defined the sequence of gene expression during the adipogenesis ex vivo of human cells from bone marrow referred to as either mesenchymal stem cells or marrow stromal cells (MSCs).
Materials and Methods: MSCs were plated at extremely low densities to generate single-cell derived colonies, and adipogenic differentiation of the colonies assayed by accumulation of fat vacuoles, time-lapse photomicroscopy, microarrays, and reverse transcriptase-polymerase chain reaction (RT-PCR) assays.
Results and Conclusions: About 30% of the colonies differentiated to adipocytes in 14 days and about 60% in 21 days. Cell proliferation was inhibited by approximately 50% in adipogenic medium. The differentiation occurred primarily at the center of the colonies, and a few adipocytes that formed near the periphery migrated toward the centers. RT-PCR assays demonstrated that the differentiation was accompanied by increases in a series of genes previously shown to increase with adipogenic differentiation: peroxisome proliferator activated receptor γ, CCAAT enhancer-binding protein α, acylCoA synthetase, lipoprotein lipase, and fatty acid binding protein 4. We also followed differentiation with microarray assays. Sixty-seven genes increased more than 10-fold at day 1 and 20-fold at day 7, 14, or 21. Many of the genes identified were previously shown to be expressed during adipocytic differentiation. However, others, such as zinc finger E-box binding protein and zinc finger protein 145, were not. This study should serve as a basis for future study to clarify the mechanisms of adipocyte differentiation of MSCs.
Deficiency of Insulin Receptor Substrate-1 Impairs Skeletal Growth Through Early Closure of Epiphyseal Cartilage
Authors: Hoshi Kazuto , Ogata Naoshi , Shimoaka Takashi , Terauchi Yasuo , Kadowaki Takashi , Kenmotsu Shin-Ichi , Chung Ung-Il , Ozawa Hedehiro , Nakamura Kozo , Kawaguchi Hiroshi 
Published: April 2006

Abstract
Morphological analyses in and around the epiphyseal cartilage of mice deficient in insulin receptor substrate-1 (IRS-1) showed IRS-1 signaling to be important for skeletal growth by preventing early closure of the epiphyseal cartilage and maintaining the subsequent bone turnover at the primary spongiosa.
Introduction: IRS-1 is an essential molecule for intracellular signaling by IGF-I and insulin, both of which are potent anabolic regulators of cartilage and bone metabolism. To clarify the role of IRS-1 signaling in the skeletal growth, morphological analyses were performed in and around the epiphyseal cartilage of mice deficient in IRS-1 (IRS-1−/−), whose limbs and trunk were 20–30% shorter than wildtype (WT) mice.
Materials and Methods: The epiphyseal cartilage and the primary spongiosa at proximal tibias of homozygous IRS-1−/− and WT male littermates were compared using histological, immunohistochemical, enzyme cytohistochemical, ultrastructural, and bone histomorphometrical analyses.
Results: In and around the WT epiphyseal cartilage, IRS-1 and insulin-like growth factor (IGF)-I receptors were widely expressed, whereas IRS-2 was weakly localized in bone cells. Chronological observation revealed that height of the proliferative zone and the size of hypertrophic chondrocytes were decreased in WT mice as a function of age, and these decreases were accelerated in the IRS-1−/− cartilage, whose findings at 12 weeks were similar to those of WT at 24 weeks. In the IRS-1−/− cartilage, proliferating chondrocytes with positive proliferating cell nuclear antigen (PCNA) or parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor immunostaining had almost disappeared by 12 weeks. Contrarily, TUNEL+ apoptotic cells were increased in the hypertrophic zone, at the bottom of which most of the chondrocytes were surrounded by the calcified matrix, suggesting the closure of the cartilage. In the primary spongiosa, bone volume, alkaline phosphatase (ALP)+ osteoblasts, TRACP+ osteoclasts, and the osteopontin-positive cement line were markedly decreased. Bone histomorphometrical parameters for both bone formation and resorption were significantly lower in IRS-1−/− mice, indicating the suppression of bone turnover.
Conclusion: The IRS-1−/− epiphyseal cartilage exhibited insufficient proliferation of chondrocytes, calcification of hypertrophic chondrocytes, acceleration of apoptosis, and early closure of the growth plate. Thus, the data strongly suggest that IRS-1 signaling is important for the skeletal growth by preventing early closure of the epiphyseal cartilage and by maintaining the subsequent bone turnover at the primary spongiosa.
Estrogen Regulates the Production of VEGF for Osteoclast Formation and Activity in op/op Mice
Authors: Kodama Ichiro , Niida Shumpei , Sanada Mitsuhiro , Yoshiko Yuji , Tsuda Mikio , Maeda Norihiko , Ohama Koso 
Published: April 2006

Abstract
op/op mice have a severe deficiency of osteoclasts because of lacking functional M-CSF that is an essential factor of osteoclast differentiation and function. We now report that OVX induces osteoclast formation and cures osteopetrosis by increasing the VEGF that regulates osteoclast formation in these mice.
Introduction: We have found that estrogen deficiency induced by ovariectomy (OVX) upregulated osteoclast formation in op/op mice. We have recently demonstrated that vascular endothelial growth factor (VEGF) could substitute for macrophage colony-stimulating factor (M-CSF) in the support of osteoclastic bone resorption in these mice. Therefore, in this study, we wished to assess the effects of VEGF on bone loss induced by OVX in these mice.
Materials and Methods: Eight-week-old op/op mice were bilateral OVX or sham-operated. Mice were killed at 8, 10, and 12 weeks of age, and femurs were removed for preparations. Some OVX mice were treated with three consecutive injections of 120 μl/body of VEGF-neutralizing antibody at 12-h intervals starting from 36 h before death at 4 weeks after OVX. VEGFR-1/Fc chimeric protein (600 μg/kg/day) or 17β-estradiol (0.16 μg/day) was administered in a dorsal subcutaneous pocket of the mice at the time of OVX. These mice were killed 2 weeks after surgery. Changes of serum levels of VEGF were measured by ELISA. Changes of mRNA levels of VEGF, Flt-1, interleukin-6, and osteoclast differentiation factor (ODF/TRANCE/RANKL) in bone tissue were measured by reverse transcriptase-polymerase chain reaction.
Results: In OVX op/op mice, trabecular bone volume of the femur was decreased, and the number of osteoclasts was significantly increased. Serum levels of VEGF were demonstrated to be higher in OVX mice than in sham-operated mice. VEGF mRNA, Flt–1 mRNA, interleukin-6 mRNA, and RANKL mRNA levels in bone tissue were elevated in OVX mice over that in sham-operated mice. The increase in osteoclast number was inhibited by VEGF antagonist treatment in OVX mice.
Conclusions: In this study, we have demonstrated that the production of VEGF and RANKL stimulated by OVX results in increased osteoclast formation in op/op mice.
Vitamin D and Calcium Supplementation Prevents Osteoporotic Fractures in Elderly Community Dwelling Residents: A Pragmatic Population-Based 3-Year Intervention Study
Authors: Larsen Erik Roj , Mosekilde Leif , Foldspang Anders 
Published: April 2006

Abstract
This study of 9605 community-dwelling residents supports that vitamin D and calcium supplementation may prevent osteoporotic fractures in elderly in a northern European region known to be deficient in vitamin D, especially during winter periods.
Introduction: We evaluated the effect of two programs for the prevention of osteoporotic fractures leading to acute hospital admission in a population of elderly community-dwelling residents.
Materials and Methods: This was a factorial, cluster-randomized, pragmatic, intervention study. We included 9605 community-dwelling residents aged 66+ years. We offered a prevention program of a daily supplement of 1000 mg of elemental calcium as calcium carbonate and 400 IU (10 μg) of vitamin D3 to a total of 4957 participants. Another program with evaluation and suggestions for the improvement of the domestic environment was offered to a total of 5063 participants. Both programs included revision of the resident's current pharmaceutical treatment. We achieved information on osteoporotic fractures in the study population from the Danish Hospital Registration Database. We defined osteoporotic fractures as low energy fractures of the proximal humerus, distal forearm, vertebral column, pelvis, cervical femur, and intertrochanteric femur.
Results: Active participation was 50.3% in the Calcium and Vitamin D Program and 46.4% in the Environmental and Health Program. We observed a 16% reduction in fracture incidence rate (relative risk [RR], 0.84; CI, 0.72–0.98; p &lt; 0.025) among male and female residents offered the Calcium and Vitamin D Program (intention-to-prevent analysis).
Conclusions: This study supports that vitamin D and calcium supplementation may prevent osteoporotic fractures in community-dwelling elderly people in a northern European region known to be deficient in vitamin D, especially during winter periods.
Relationship Between Changes in Biochemical Markers of Bone Turnover and BMD to Predict Vertebral Fracture Risk
Authors: Sarkar Somnath , Reginster Jean-Yves , Crans Gerald G , Diez-Perez Adolfo , Pinette Karen V , Delmas Pierre D 
Published: April 2006

Abstract
The change in BMD is a poor predictor of vertebral fracture risk after raloxifene treatment. One-year percent change in bone turnover and BMD was used to predict vertebral fracture risk. The percent change in osteocalcin was determined to be a better predictor of vertebral fracture risk than BMD.
Introduction: The association between baseline BMD and fracture risk is well understood. However, the relationship between changes in BMD and fracture risk is not well defined. It has previously been demonstrated that BMD change was a poor predictor of vertebral fracture risk in raloxifene-treated women, whereas bone turnover markers were significantly associated with fracture risk. In the current analysis, we explore the prediction of vertebral fracture risk using changes in both BMD and bone turnover.
Materials and Methods: The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a randomized, placebo-controlled trial of 7705 women with osteoporosis treated with raloxifene 60 or 120 mg/day for 3 years. Markers of bone turnover were measured in one-third of the study population (n = 2503), and the present analyses include these women. Logistic regression models were constructed using one-year percent changes in BMD and bone turnover and relevant baseline demographics to predict the risk of vertebral fracture with pooled raloxifene therapy at 3 years. All covariates were standardized before modeling to facilitate direct comparisons between changes in BMD and bone turnover.
Results and Conclusion: Prevalent vertebral fracture status (p &lt; 0.0001), baseline lumbar spine BMD (p &lt; 0.0001), and number of years postmenopausal (p = 0.0005) were independent predictors of fracture risk in raloxifene-treated patients. Therapy-by-change in femoral neck BMD (p = 0.02) and therapy-by-change in osteocalcin (OC; p = 0.01) were also significant for all treatment groups, indicating that changes in BMD and OC have different effects on fracture risk for the placebo and pooled raloxifene groups. The final model included significant baseline variables and change in OC (p = 0.01), whereas change in femoral neck BMD was not significant. After adjustment of each significant baseline variable, the percent change in OC was better able to predict the reduction in vertebral fracture risk than the percent change in femoral neck BMD in patients treated with raloxifene.
Effect of 6-Month Whole Body Vibration Training on Hip Density, Muscle Strength, and Postural Control in Postmenopausal Women: A Randomized Controlled Pilot Study
Authors: Verschueren Sabine MP , Roelants Machteld , Delecluse Christophe , Swinnen Stephan , Vanderschueren Dirk , Boonen Steven 
Published: April 2006

Abstract
High-frequency mechanical strain seems to stimulate bone strength in animals. In this randomized controlled trial, hip BMD was measured in postmenopausal women after a 24-week whole body vibration (WBV) training program. Vibration training significantly increased BMD of the hip. These findings suggest that WBV training might be useful in the prevention of osteoporosis.
Introduction: High-frequency mechanical strain has been shown to stimulate bone strength in different animal models. However, the effects of vibration exercise on the human skeleton have rarely been studied. Particularly in postmenopausal women—who are most at risk of developing osteoporosis—randomized controlled data on the safety and efficacy of vibration loading are lacking. The aim of this randomized controlled trial was to assess the musculoskeletal effects of high-frequency loading by means of whole body vibration (WBV) in postmenopausal women.
Materials and Methods: Seventy volunteers (age, 58–74 years) were randomly assigned to a whole body vibration training group (WBV, n = 25), a resistance training group (RES, n = 22), or a control group (CON, n = 23). The WBV group and the RES group trained three times weekly for 24 weeks. The WBV group performed static and dynamic knee-extensor exercises on a vibration platform (35–40 Hz, 2.28–5.09g), which mechanically loaded the bone and evoked reflexive muscle contractions. The RES group trained knee extensors by dynamic leg press and leg extension exercises, increasing from low (20 RM) to high (8 RM) resistance. The CON group did not participate in any training. Hip bone density was measured using DXA at baseline and after the 6-month intervention. Isometric and dynamic strength were measured by means of a motor-driven dynamometer. Data were analyzed by means of repeated measures ANOVA.
Results: No vibration-related side effects were observed. Vibration training improved isometric and dynamic muscle strength (+15% and + 16%, respectively; p &lt; 0.01) and also significantly increased BMD of the hip (+0.93%, p &lt; 0.05). No changes in hip BMD were observed in women participating in resistance training or age-matched controls (−0.60% and −0.62%, respectively; not significant). Serum markers of bone turnover did not change in any of the groups.
Conclusion: These findings suggest that WBV training may be a feasible and effective way to modify well-recognized risk factors for falls and fractures in older women and support the need for further human studies.
CYP3A4 is a Human Microsomal Vitamin D 25-Hydroxylase
Authors: Gupta Ram P , Hollis Bruce W , Patel Shailendra B , Patrick Kennerly S , Bell Norman H 
Published: April 2006

Abstract
The human hepatic microsomal vitamin D 25-hydroxylase protein and gene have not been identified with certainty. Sixteen hepatic recombinant microsomal enzymes were screened for 25-hydroxylase activity; 11 had some 25-hydroxylase activity, but CYP3A4 had the highest activity. In characterized liver microsomes, 25-hydroxylase activity correlated significantly with CYP3A4 testosterone 6β-hydroxylase activity. Activity in pooled liver microsomes was inhibited by known inhibitors of CYP3A4 and by an antibody to CYP3A2. Thus, CYP3A4 is a hepatic microsomal vitamin D 25-hydroxylase.
Introduction: Studies were performed to identify human microsomal vitamin D-25 hydroxylase.
Materials and Methods: Sixteen major hepatic microsomal recombinant enzymes derived from cytochrome P450 cDNAs expressed in baculovirus-infected insect cells were screened for 25-hydroxylase activity with 1α-hydroxyvitamin D2 [1α(OH)D2], 1α-hydroxyvitamin D3 [1α(OH)D3], vitamin D2, and vitamin D3 as substrates. Activity was correlated with known biological activities of enzymes in a panel of 12 characterized human liver microsomes. The effects of known inhibitors and specific antibodies on activity also were determined.
Results: CYP3A4, the most abundant cytochrome P450 enzyme in human liver and intestine, had 7-fold greater activity than that of any of the other enzymes with 1α(OH)D2 as substrate. CYP3A4 25-hydroxylase activity was four times higher with 1α(OH)D2 than with 1α(OH)D3 as substrate, was much less with vitamin D2, and was not detected with vitamin D3. 1α(OH)D2 was the substrate in subsequent experiments. In a panel of characterized human liver microsomes, 25-hydroxylase activity correlated with CYP3A4 testosterone 6β-hydroxylase activity (r = 0.93, p &lt; 0.001) and CYP2C91 diclofenac 4′-hydroxylase activity (r = 0.65, p &lt; 0.05), but not with activity of any of the other enzymes. Activity in recombinant CYP3A4 and pooled liver microsomes was dose-dependently inhibited by ketoconazole, troleandomycin, isoniazid, and α-naphthoflavone, known inhibitors of CYP3A4. Activity in pooled liver microsomes was inhibited by antibodies to CYP3A2 that are known to inhibit CYP3A4 activity.
Conclusion: CYP3A4 is a vitamin D 25-hydroxylase for vitamin D2 in human hepatic microsomes and hydroxylates both 1α(OH)D2 and 1α(OH)D3.