bluuebunny/crossref_metadata_2025_split huggingface dataset:
Skeletal response to recombinant human growth hormone (rhGH) in children treated with long-term corticosteroids
Authors: Sanchez Cheryl P. , Goodman William G. , Brandli David , Goldenhersh Margaret , Murray Carol , Carlton Esther , Hahn Theodore , Salusky Isidro B. 
Published: February 2010

Abstract
Corticosteroid therapy causes osteopenia and growth retardation in children; such changes are associated with diminished rates of bone formation and turnover. Since growth hormone activates bone remodeling, the biochemical and skeletal responses to rhGH were evaluated in four pediatric patients, aged 12.8 ± 3 years, with long-term corticosteroid use (5 ± 2 years). Recombinant human growth hormone (rhGH), 0.125 mg/kg, was given 3 times/week by subcutaneous injection for 12 months. Iliac crest bone biopsies were obtained after double tetracycline labeling before and at the end of rhGH therapy; serum levels of calcium, phosphorus, alkaline phosphatase, parathyroid hormone (intact), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D3, osteocalcin (BGP), and insulin-like growth factor-1 (IGF-1) were measured every 3 months during the treatment period. The average dose of prednisone was 0.24 ± 0.05 mg/kg/day initially, and this did not change during the study. Serum calcium, phosphorus, alkaline phosphatase, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D3, and BGP were unchanged during the rhGH therapy, but the serum IGF-1 level increased by 71%, p &lt; 0.01. Eroded bone perimeter and cancellous bone area did not change significantly during rhGH therapy. Bone formation rates rose from 423 ± 475 to 781 ± 407 μm2/mm2/day, p &lt; 0.05, and the length of double tetracycline-labeled bone perimeter increased by 85%, p &lt; 0.05. The bone formation rate in the growth hormone group exceeded the values of an age-matched reference group (143 ± 3 years), 780 ± 407 μm2/mm2/day versus 411 ± 479 μ m2/mm2/day, p &lt; 0.05. Thus, rhGH therapy increases osteoblastic activity, bone formation, and possibly bone turnover despite continued and prolonged corticosteroid administration in children.
Expression and secretion of parathyroid hormone-related protein by human bone-derived cells in vitro: Effects of glucocorticoids
Authors: Walsh C.A. , Birch M.A. , Fraser W.D. , Lawton R. , Dorgan J. , Walsh S. , Sansom D. , Beresford J.N. , Gallagher J.A. 
Published: February 2010

Abstract
We investigated the production of parathyroid hormone-related protein (PTHrP) by cells derived from explants of human bone. Using an immunoradiometric assay (IRMA), PTHrP was detected in conditioned medium from cultures of bone-derived cells from 6 of 7 patients investigated in this study. PTHrP mRNA was identified in human bone cells using reverse transcriptase-linked polymerase chain reaction (RT-PCR) and by Northern analysis. Transcripts for PTHrP were detected in a purified population of alkaline phosphatase positive cells isolated from human bone marrow cultures by flow cytometry, confirming the expression of PTHrP mRNA by cells of the osteoblastic lineage. Production of PTHrP was inhibited by 10−6 M of the glucocorticoids, prednisolone and desacetylated deflazacort, in a dose-dependent manner. In addition, RT-PCR followed by Southern blot analysis detected a decrease in steady-state PTHrP mRNA in cultures of human bone-derived cells treated with 10−6 M prednisolone.
In vivo evidence for progressive activation of parathyroid hormone-related peptide gene transcription with tumor growth and stimulation of osteoblastic bone formation at an early stage of humoral hypercalcemia of cancer
Authors: Yamato Hideyuki , Nagai Yumiko , Inoue Daisuke , Ohnishi Yasuyuki , Ueyama Yoshito , Ohno Hideto , Matsumoto Toshio , Ogata Etsuro , Ikeda Kyoji 
Published: February 2010

Abstract
The present study was undertaken to clarify in vivo the temporal profile of parathyroid hormone-related peptide (PTHRP) gene expression as well as bone histomorphometric features as a function of tumor growth, using an athymic rat model associated with humoral hypercalcemia of malignancy (HHM). Tumor-bearing animals exhibited hypercalcemia, hypophosphatemia, and increased circulating levels of PTHRP, and died within 3 weeks. Steady-state PTHRP mRNA levels and the transcription rate of PTHRP gene in the tumors were markedly increased with tumor growth. RNAse mapping analysis revealed that both upstream and downstream promoters of the human PTHRP gene were utilized in the tumors and became progressively activated with time. Bone histomorphometric analysis showed that osteoclastic bone resorption was progressively increased throughout the course, whereas osteoblastic bone formation was stimulated more than 2-fold at a very early stage (day 6 after tumor implantation) and then markedly suppressed thereafter on day 12 and day 18 compared with age-matched control animals. These results provide in vivo evidence that PTHRP gene transcription is progressively activated with tumor growth and that activation of osteoblasts does occur at a very early phase of HHM syndrome in contrast to the marked suppression of bone formation at later stages.
Calcitonin receptor isoforms in mouse and rat osteoclasts
Authors: Ikegame Mika , Rakopoulos Maryann , Zhou Hong , Houssami Souheir , Martin John T. , Moseley Jane M. , Findlay David M. 
Published: February 2010

AbstractCalcitonin receptors (CTRs) from several species have recently been cloned and shown to belong to the 7 transmembrane domain class of receptor. We have identified two CTR isoforms in the rat, termed C1a and C1b, identical except for a 37-amino-acid insert in the putative second extracellular domain of C1b. To examine the CTR isoforms expressed in rat and mouse osteoclasts and the time course of their appearance in culture, bone marrow cells were cultured from C57/B16J mice and osteoclasts were isolated from newborn rat long bones. CTR-bearing cells were detected by autoradiography of 125I-salmon CT binding, and cultures were stained for tartrate-resistant acid phosphatase (TRAP). RNA was extracted from parallel cultures, and CTR mRNA was detected by Northern blot analysis, using a rat digoxigenin-labeled riboprobe. Characterization of mRNA for the CTR isoforms was by reverse transcription-polymerase chain reaction (RT-PCR) using primer sets and oligonucleotide probes specific for the two rat receptor isoforms. In mouse marrow cultures, TRAP positive mononucleated cells were present by day 2 of culture at which time CTR positive cells were few. Multinucleated cells with both these markers were seen only from day 4 and later. By Northern analysis of total RNA, a band of approximately 4 kb could be detected in day 4 and later cultures. RT-PCR showed that mouse homologs of both C1a and C1b mRNA species were expressed early in cultures of mouse osteoclasts, although at each time C1a appeared to predominate. RNA was also extracted from osteoclasts freshly isolated from neonatal rat long bone osteoclasts. Northern blot analysis suggested that these preparations contained less CTR mRNA than the developing mouse osteoclast preparations. RT-PCR indicated that both receptor isoforms were expressed in rat osteoclasts.
Thiazide diuretics and fractures: Can meta-analysis help?
Authors: Dr. Menzies G. Jones , Nguyen Tuan , Sambrook Philip N. , Eisman John A. 
Published: February 2010

Abstract
Published observational estimates of the effect of thiazide diuretics on osteoporotic fracture risk vary from a 70% reduction to a 60% increase but there have been no randomized controlled trials. The aims of this study were to use the technique of meta-analysis to attempt to resolve this conflict and to explore whether duration and/or dose of therapy has an effect on osteoporotic fracture risk. The data sources utilized were Medline and Excerpta Medica databases supplemented by reviews and back references. A total of 18 observational studies that looked at the relationship between diuretics and fracture were located, of which 13, involving 29,600 subjects, had extractable data on thiazides and fracture occurrence. Current thiazide users were protected against hip fracture (OR 0.82, 95% Cl 0.73–0.91). Thiazide use of long duration may be protective (OR 0.82, 95% Cl 0.62–1.08) but not short duration (OR 1.23, 95% Cl 0.99–1.54). The size of this effect, which compares favorably to other interventions, indicates that a randomized controlled trial to resolve the problem of potential confounders and safety profile would require a minimum of 7000 person-years of observation in those at highest risk of fracture (women aged 80 or over) which is unlikely to be pursued at the present time. The results of this meta-analysis indicate that current thiazide users have a 20% reduction in fracture risk and that long-term use may reduce fractures by a similar amount These results suggest, in the absence of a suitably designed large randomized controlled trial, that thiazides should be considered as part of an approach to osteoporotic fracture prevention, particularly in hypertensive subjects.
Estimation of structural and geometrical properties of cortical bone by computerized tomography in 78-year-old women
Authors: Cheng Sulin , Toivanen Jari Antero , Suominen Harri , Toivanen Jarmo Tapani , Timonen Jussi 
Published: February 2010

Abstract
The structural and geometrical properties of the tibia shaft were investigated at two sections by means of computerized tomography (CT) in 78-year-old women with high (n = 19) and low (n = 17) calcaneal bone mineral density (BMD, g/cm3) previously measured by 125I-photon absorption. The high BMD group had a 20–21% higher tibial BMD and 9–12% higher bone cross-sectional area than was observed in the low BMD group. The distribution of bone mass indicated that the low BMD group had lost bone mainly from the endosteal surface, especially in the anterior part of the tibia. However, both groups had a similar basic pattern of mass distribution at the measured sections. The high BMD group had higher moments of inertia at the upper section than the low BMD group. The differences between the groups were more pronounced when only the high density areas were included. At the lower section, the differences between the groups also appeared significant at the high density levels. There were no group differences in the area moments of inertia. The results suggest that the true distribution of bone mass should be taken into account in determining the moments of inertia. In the tibia, determination of the cross-sectional mass distribution of bone combined with BMD should have a better discriminatory capability than BMD only in studying bone strength and fracture risk.
Risk factors for renal osteodystrophy: A multivariant analysis
Authors: Pei York , Hercz Gavril , Greenwood Celia , Segre Gino , Manuel Arif , Saiphoo Carl , Fenton Stanley , Sherrard Donald 
Published: February 2010

Abstract
To assess the risk factors associated with renal osteodystrophy, we examined the database of 256 patients who were prospectively studied in three Toronto dialysis centers between October of 1987 and 1989. The potential risk factors examined included age, sex, type and duration of dialysis, type and dose of phosphate binders, vitamin D treatment, and history of diabetes mellitus, renal allograft failure, parathyroidectomy, and bilateral nephrectomy. All patients had undergone a bone biopsy and were categorized into one of four disease groupings: (1) osteitis fibrosa and mixed bone disease, (2) aluminum bone disease, (3) mild bone disorder, and (4) aplastic bone disorder. The mean (±SD) age of the patients at bone biopsy was 57 ± 15 years, and 62% were men. Forty-five percent of patients were treated by hemodialysis and 55% by peritoneal dialysis. The mean duration of dialysis was 4 ± 4 years. Twenty-five percent were also diabetic. The most common disorder was the aplastic (or “adynamic”) bone disorder, found in 34% of patients. Aluminum bone disease was found in 27%, osteitis fibrosa or mixed bone disease in 27%, and mild bone disorder in 12% of patients. Cumulative intake of aluminum gels was associated with aluminum bone disease, whereas peritoneal dialysis with supraphysiologic calcium concentrations, ingestion of calcium carbonate, and diabetes mellitus were associated with both mild bone disorder and aplastic bone disorder. These three latter risk factors may be important in predisposing patients to a low bone turnover state through modulation of parathyroid hormone secretion. Thus, recent increases in the frequencies of these risk factors in dialysis patients are associated with a high prevalence of aplastic bone disorder. The clinical significance of this bone disorder remains to be defined.
Characterization of structural sequences in the chicken osteocalcin gene: Expression of osteocalcin by maturing osteoblasts and by hypertrophic chondrocytes in vitro
Authors: Neugebauer Brigitte M. , Moore Mark A. , Broess Martin , Dr. Gerstenfeld L.C. , Dr. Hauschka P.V. 
Published: February 2010

Abstract
Osteocalcin is one of the major noncollagenous proteins specific to mineralized connective tissues of vertebrates. A cDNA clone encoding the chicken osteocalcin gene was isolated, and the complete coding sequence for the 97-amino-acid pre-pro-osteocalcin was deduced. The 48-amino-acid pre-pro-peptide contains the expected hydrophobic leader sequence and the dibasic Lys-Arg sequence preceding the NH2-terminal His of the mature 49-amino-acid chicken osteocalcin, which is believed to be necessary for pro-peptide cleavage. The pro-peptide sequence also contains the expected motif of polar and hydrophobic residues, including Phe at −16, which targets vitamin K-dependent γ-carboxylation of the three specific Glu residues at positions 17, 21, and 24 in the mature protein. Northern blots of total RNA were prepared from embryonic and adult chicken tissues (bone, brain, heart, intestine, kidney, muscle) and probed with chicken osteocalcin cDNA. The appearance of a single 0.5 kb mRNA species confirms that bone is the major site of osteocalcin expression in vivo. In primary osteoblasts isolated from 17-day embryonic chicken calvaria, an osteocalcin mRNA of similar size is expressed concurrently with culture mineralization in vitro. Hypertrophic chondrocytes from 12-day ventral vertebrae and from the cephalic half of 17-day caudal sternae also express osteocalcin mRNA, but nonhypertrophic chondrocytes from the caudal half of 17-day sternae do not express osteocalcin mRNA.
Fluoride increases tyrosine kinase activity in osteoblast-like cells: Regulatory role for the stimulation of cell proliferation and Pi transport across the plasma membrane
Authors: Burgener D. , Bonjour J.-P. , Dr. Caverzasio Joseph 
Published: February 2010

Abstract
Fluoride is one of the most effective agents for the treatment of vertebral osteoporosis because of its ability to increase osteoblast proliferation. The present study further investigates the role of protein tyrosine phosphorylation previously suggested to mediate the mitogenic effect of fluoride on bone-forming cells. The activity of the plasma membrane Na-coupled Pi transport system was monitored to assess the relationship between alterations in tyrosine phosphorylation and osteoblast activity induced by fluoride. The results indicate that vanadate, a selective inhibitor of tyrosine phosphatase, mimicked the stimulatory effect of fluoride on Pi transport. The change in Pi transport induced by fluoride was dose dependently inhibited by genistein, a potent inhibitor of tyrosine kinase. Genistein also inhibited the change in cell proliferation induced by fluoride. Associated with these observations, tyrosine phosphorylation activity was significantly increased in subcellular fractions isolated from UMR-106 cells treated with fluoride as compared with those isolated from vehicle-treated cells. This change in tyrosine phosphorylation activity was markedly blunted when genistein was added to the kinase assay buffer. It was not associated with any alteration in specific tyrosine phosphatase activity. There was also no evidence of a direct effect of fluoride on tyrosine phosphatase activity in isolated plasma membrane of UMR-106 cells. In conclusion, the results of the present study suggest that fluoride enhances protein tyrosine phosphorylation in osteoblast-like cells by enhancing tyrosine kinase activity. The results further support the hypothesis that this signal transduction mechanism is involved in the osteogenic effects of fluoride.
Development and characterization of a conditionally immortalized human fetal osteoblastic cell line
Authors: Dr. Harris Steven A. , Enger Robert J. , Riggs Lawrence B. , Spelsberg Thomas C. 
Published: February 2010

Abstract
We report the establishment of a human fetal osteoblast cell line derived from biopsies obtained from a spontaneous miscarriage. Primary cultures isolated from fetal tissue were transfected with a gene coding for a temperature-sensitive mutant (tsA58) of SV40 large T antigen along with a gene coding for neomycin (G418) resistance. Individual neomycin resistant colonies were screened for alkaline phosphatase (AP)-specific staining. The clone with the highest AP level, hFOB 1.19, was examined further for other osteoblast phenotypic markers. Incubation of hFOB cells at the permissive temperature (33.5°C) resulted in rapid cell division, whereas little or no cell division occurred at the restrictive temperature (39.5°C). Both AP activity and osteocalcin (OC) secretion increased in a dose-dependent manner following dihydroxyvitamin D3 (1,25-D3) treatment when cultured at either temperature. However, AP and 1,25-D3-induced OC levels were elevated in confluent hFOB cells cultured at 39.5°C compared with 33.5°C. Treatment of hFOB cells with 1–34 parathyroid hormone (PTH) resulted in an increase in cAMP levels. Upon reaching confluence, hFOB cultures went through programmed differentiation and formed mineralized nodules as observed by von Kossa staining. Further, immunostaining of postconfluent, differentiated hFOB cells showed that high levels of osteopontin, osteonectin, bone sialoprotein, and type I collagen were expressed. Therefore, the clonal cell line hFOB 1.19 provides a homogeneous, rapidly proliferating model system to study certain stages of human osteoblast differentiation.
Effects of 24r,25-dihydroxyvitamin D3 in combination with 1α-hydroxyvitamin D3 in predialysis renal insufficiency: Biochemistry and histomorphometry of cancellous bone
Authors: Birkenhäger-Frenkel D.H. , Pols H.A.P. , Zeelenberg J. , Eijgelsheim J.J. , Schot R. , Nigg A.L. , Weimar W. , Mulder P.G.H. , Birkenhäger J.C. 
Published: February 2010

Abstract
The effect of combined administration of 24R,25-dihydroxyvitamin D3 (24,25-(OH)2D3) and 1α-hydroxyvitamin D3 (1α-(OH)D3) was studied in 24 non-dialyzed patients with chronic renal insufficiency (CRI), matched pair-wise as to age, sex, and creatinine clearance (Cr.cl). Low Ca intake had been supplemented beforehand. Then, 1α-(OH)D3 (mean dose 0.55 μg daily) was given orally to all patients for 3 months (T0 to T3). Subsequently, patients were assigned randomly to 6 months further treatment either with 1α-(OH)D3 alone (Group A) or with 1α-(OH)D3 plus a high dosage of 24,25-(OH)2D3 (50 μg orally, twice weekly) (Group B). Histomorphometry was performed at T0T3, and T9. In both groups iPTH was equally suppressed, into the lower normal range. Whereas in Group A, serum Ca rose steadily and Cr.cl declined, in Group B both parameters levelled off between T6 and T9. At T9, in Group A the elevated resorption and osteoid indices had normalized markedly, but osteoblasts (Ob.Pm) and mineralizing boundaries (M.Bd) were depressed considerably between T3 and T9. In contrast, in Group B, preservation of Ob.Pm and improved mineralizing activity were observed (M.Bd at T9 &gt; T3 &gt; T0). Resorption indices hardly changed. In the patients with high Ob.Pm at T0, cancellous bone area increased significantly. This was not observed in Group A. Thus, in Group B, osteoblast recruitment appeared maintained and M.Bd appeared normalized. Decline of remodeling toward an adynamic state with an increased risk of hypercalcemia appeared prevented.
Spontaneous postmenopausal bone loss in different skeletal areas—followed up for 15 years
Authors: Hansen M.A. , Overgaard K. , Christiansen C. 
Published: February 2010

Abstract
We examined the spontaneous bone loss in two populations of healthy postmenopausal women, who were followed for 9.5 and 14.5 years without any treatment influencing the calcium metabolism. The bone mass was measured in different skeletal areas: the distal forearm, the lumbar spine, the proximal femur, and the total skeleton. The spontaneous bone loss in the distal forearm, the lumbar spine, and the total skeleton was fitted to an exponential model as a function of years since menopause. The overall bone loss averaged 20–25% of premenopausal bone mass 16 years after menopause. The patterns of bone loss were, however, different for the axial and the peripheral skeleton. Thus, the bone loss in the distal forearm approached a more linear model with a more consistent bone loss throughout the observation period. In contrast, the lumbar spine showed no significant loss 8 years after menopause. This arrest in bone loss could not be explained by the presence of degenerative changes in the lumbar spine and/or aortic calcifications, although these changes significantly contributed to 14% increased bone mineral density (p &lt; 0.001). We conclude that bone loss averages 20–25% over the initial 16 years of menopause regardless of skeletal site and that patterns of bone loss are different in the axial and peripheral skeleton.
In vivo inhibition of localized bone resorption by human recombinant interleukin-1 receptor antagonist
Authors: Chole Richard A. , Faddis Brian T. , Tinling Steven P. 
Published: February 2010

Abstract
Interleukin-1 (IL-1) has been implicated as a primary mediator of bone remodeling; it is a powerful activator of bone resorption both in vivo and in vitro. However, there is no direct evidence that IL-1 plays a role in physiological bone modeling or remodeling. Interleukin-1 receptor antagonist (IL-1ra) is a member of the IL-1 family, which bind to IL-1 receptors and blocks the action of IL-1α and IL-1β. We have previously shown that IL-1ra blocks IL-1—induced bone resorption in vitro. Evidence is reported here that human recombinant IL-1ra (hrIL-1ra) inhibits strain-induced modeling in the gerbil auditory bulla while having no significant effect on apposition rate. Pressurization of the auditory bulla to 10 mm Hg above atmospheric pressure increased osteoclast surface from 3.62 to 19.14%. Infusion of hrIL-1ra during pressurization resulted in significant inhibition of osteoclast surface on the pressurized side. These findings suggest that IL-1 is a physiological mediator of bone modeling and that hrIL-1ra inhibits resorption but not apposition in the auditory bulla model.