bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Teriparatide [Human Parathyroid Hormone (1–34)] Therapy on Bone Density in Men With Osteoporosis
Authors: Orwoll ES , Scheele WH , Paul S , Adami S , Syversen U , Diez-Perez A , Kaufman J-M , Clancy AD , Gaich GA 
Published: April 2006

Abstract
Teriparatide [rhPTH(1–34)] increases bone mineral density and reduces the risk of vertebral fracture in women. We randomized 437 men with spine or hip bone mineral density more than 2 SD below the young adult male mean to daily injections of placebo, teriparatide 20 μg, or teriparatide 40 μg. All subjects also received supplemental calcium and vitamin D. The study was stopped after a median duration of 11 months because of a finding of osteosarcomas in rats in routine toxicology studies. Biochemical markers of bone formation increased early in the course of therapy and were followed by increases in indices of osteoclastic activity. Spine bone mineral density was greater than in placebo subjects after 3 months of teriparatide therapy, and by the end of therapy it was increased by 5.9% (20 μg) and 9.0% (40 μg) above baseline (p &lt; 0.001 vs. placebo for both comparisons). Femoral neck bone mineral density increased 1.5% (20 μg; p = 0.029) and 2.9% (40 μg; p &lt; 0.001), and whole body bone mineral content increased 0.6% (20 μg; p = 0.021) and 0.9% (40 μg; p = 0.005) above baseline in the teriparatide subjects. There was no change in radial bone mineral density in the teriparatide groups. Bone mineral density responses to teriparatide were similar regardless of gonadal status, age, baseline bone mineral density, body mass index, smoking, or alcohol intake. Subjects experienced expected changes in mineral metabolism. Adverse events were similar in the placebo and 20-μg groups, but more frequent in the 40-μg group. This study shows that teriparatide treatment results in an increase in bone mineral density and is a potentially useful therapy for osteoporosis in men.
Long-Term Variability of Markers of Bone Turnover in Postmenopausal Women and Implications for Their Clinical Use: The OFELY Study
Authors: Garnero Patrick , Mulleman Dennis , Munoz Francoise , Sornay-Rendu Elisabeth , Delmas Pierre D 
Published: April 2006

AbstractBone marker variability has raised concern for its use in individual patients. Serum osteocalcin (formation) and CTX (resorption) were measured every year for 4 years in 268 postmenopausal women. Seventy percent to 80% of women classified as having high bone turnover at baseline were similarly classified by the same methods 4 years later.Introduction: High bone marker levels are a risk factor for osteoporosis in postmenopausal women, but variability of measurements has raised doubts about their clinical use in an individual patient.Methods: We studied 268 untreated postmenopausal women (50–81 years of age) belonging to a population-based prospective cohort. We collected fasting morning blood samples every year for 4 years to measure serum intact osteocalcin (OC) and serum C-terminal cross-linked telopeptide of type I collagen (CTX) as bone formation and resorption markers, respectively.Results: Serum OC and CTX remained stable during follow-up (+1.2%/year, p = 0.003 and −0.13%/year, p = 0.70 for OC and S-CTX, respectively). At baseline, women were classified as having low (tertile 1), intermediate (tertile 2), or high (tertile 3) bone turnover. Agreement of classification between baseline and 4-year measurements was moderate (κ [95% CI]: 0.51 [0.43–0.59] and 0.52 [0.44–0.60] for OC and S-CTX, respectively). Less than 10% of women in tertile 1 or 3 of either marker at baseline were found in the opposite tertile 4 years later. When the two markers were combined, only 2% of women at high turnover at baseline—defined as OC and/or S-CTX in tertile 3—were classified at low turnover 4 years later. Among women classified at high bone turnover at baseline (tertile 3), 70–80 % were also found at high turnover 4 years later. Among women in tertile 2, only 51% and 43% for OC and CTX, respectively, remained in the same tertile at the second measurement.Conclusions: Serum levels of bone formation and resorption markers are stable over 4 years in postmenopausal women, on average. The majority of women classified as having high bone turnover were similarly classified by the same methods 4 years later. However, 20–30 % of these women at risk for fracture would be incorrectly classified, suggesting that further investigation would be required to reduce the number of patients who would be treated unnecessarily if the decision was made on bone marker measurement. For women with intermediate levels, classification may be improved by a second measurement or by combining two markers.
Perturbations in Bone Formation and Resorption in Insulin-Like Growth Factor Binding Protein-3 Transgenic Mice
Authors: Silha Josef V , Mishra Suresh , Rosen Clifford J , Beamer Wesley G , Turner Russell T , Powell David R , Murphy Liam J 
Published: April 2006

Abstract
IGF-I and their binding proteins are important in bone health. Examination of BMD, osteoblast proliferation, and markers of bone resorption in transgenic mice that constitutively overexpress IGFBP-3 indicates that overexpression of IGFBP-3 increases osteoclast number and bone resorption, impairs osteoblast proliferation, and has a significant negative effect on bone formation.
Introduction: Low serum insulin-like growth factor I (IGF-I) levels correlate with an increased risk of osteoporotic fractures. Serum IGF-I is largely bound to IGF-binding protein-3 (IGFBP-3), which can inhibit IGF-I action and enhance delivery of IGF-I to tissues. Its role in bone biology is unclear.
Methods: Bone mineral density (BMD), osteoblast proliferation, and markers of bone resorption were examined in transgenic (Tg) mice that constitutively overexpressed human IGFBP-3 cDNA driven by either the cytomegalovirus (CMV) or phosphoglycerate kinase (PGK) promoter.
Results: Cultured calvarial osteoblasts from Tg mice expressed the transgene and grew more slowly than cells from wild-type (Wt) mice, and the mitogenic response to IGF-I was attenuated in osteoblasts from Tg mice. Total volumetric BMD and cortical BMD, measured in the femur using peripheral quantitative computed tomography (pQCT) were significantly reduced in both Tg mouse strains compared with Wt mice. PGKBP-3 Tg mice showed the most marked reduction in bone density. Osteocalcin levels were similar in Wt and CMVBP-3 Tg mice but were significantly reduced in PGKBP-3 Tg mice. Urinary deoxypyridinoline and osteoclast perimeter, markers of bone resorption, were significantly increased in both Tg mouse strains compared with Wt mice. Using double labeling with tetracycline, we demonstrated that pericortical and endocortical mineral apposition rate was significantly reduced in PGKBP-3 Tg mice compared with Wt mice.
Conclusions: These data show that overexpression of IGFBP-3 increases osteoclast number and bone resorption, impairs osteoblast proliferation, and has a significant negative effect on bone formation.
Regulation of the Murine TRACP Gene Promoter
Authors: Cassady AI , Luchin A , Ostrowski MC , Hume DA 
Published: April 2006

Abstract
The activity of the TRACP promoter has been investigated as a model of gene regulation in osteoclasts. The murine TRACP gene promoter contains potential binding sites for a number of transcription factors in particular, candidate sites for the Ets factor PU.1 and for the microphthalmia transcription factor (MiTF). These are of relevance to osteoclast biology because the PU.1 knockout mouse has an osteopetrotic phenotype, and MiTF, when mutated in the mi/mi mouse, also results in osteopetrosis. The binding sites for both of these factors have been identified, and they have been determined to be functional in regulating TRACP expression. A novel assay system using the highly osteoclastogenic RAW/C4 subclone of the murine macrophage cell line RAW264.7 was used to perform gene expression experiments on macrophage and osteoclast cell backgrounds. We have shown that TRACP expression is a target for regulation by the macrophage/osteoclast transcription factor PU.1 and the osteoclast commitment factor MiTF and that these factors act synergistically in regulating this promoter. This directly links two controlling factors of osteoclast differentiation to the expression of an effector of cell function.
Potential Function for the ROS-Generating Activity of TRACP
Authors: Halleen Jussi M , Räisänen Seija R , Alatalo Sari L , Väänänen H Kalervo 
Published: April 2006

Abstract
TRACP is an enzyme with unknown biological function. It is expressed primarily in bone-resorbing osteoclasts and activated macrophages. In addition to its phosphatase activity, TRACP is capable of generating reactive oxygen species (ROS). In resorbing osteoclasts, TRACP is localized in transcytotic vesicles transporting bone matrix degradation products from the resorption lacuna to a functional secretory domain in the basolateral membrane. ROS generated by TRACP are capable of destroying organic bone matrix components, suggesting that they may be targeted to further destroy initial matrix degradation products in the transcytotic vesicles. The transcytotic route of osteoclasts is analogous with the antigen presentation route of macrophages transporting endocytosed foreign material into cell surface for presentation to other cells of the immune system. Macrophages overexpressing TRACP have elevated levels of intracellular ROS. In alveolar macrophages, TRACP is colocalized with endocytosed Staphylococcus aureus, a pathogen whose clearance is reduced in TRACP-deficient mice, suggesting that ROS generated by TRACP may be targeted to destroy foreign material in the antigen presentation route of macrophages. These data suggest that the ROS generating activity of TRACP may have an important role both in bone resorption and in the immune defense system.
Osteoporosis in Patients on Long-Term Home Parenteral Nutrition: A Longitudinal Study
Authors: Cohen-Solal M , Baudoin C , Joly F , Vahedi K , D'Aoust L , De Vernejoul Mc , Messing B 
Published: April 2006

Abstract
The prevalence of osteoporosis was investigated in 88 patients with intestinal failure (IF). Osteoporosis was found in 67%, dependent of body mass index and age when IF occurred. In 56 patients on HPN, followed prospectively, changes in bone density were dependent on the duration of HPN; older patients had a higher increase.
Introduction: It has been suggested that low bone mass and negative bone balance may occur in adult patients receiving home parenteral nutrition (HPN). The aim of this study was to assess prospectively the prevalence of osteoporosis in intestinal failure (IF) patients and the changes in bone mineral density in those on long-term HPN and to analyze the factors that may influence the occurrence and evolution of osteoporosis.
Materials and Methods: Bone mineral density was measured at the lumbar spine and femoral neck in 88 IF patients.
Results: At the first bone mineral density determination (baseline), the prevalence of osteoporosis was 67% in this population (median age, 52 years). Ten percent of the patients with osteoporosis experienced fragility fractures. Osteoporosis was independent of age and gender but occurred earlier in patients who had received corticosteroids. At baseline, the lumbar Z-score was positively correlated mainly to body mass index and age when IF occurred; these two parameters explained 34% of the Z-score. Repeated measurements were performed in 56 patients during long-term HPN (mean duration, 5.5 ± 1.2 years). The changes in Z-score at the lumbar spine were dependent on the age when IF occurred and on the duration of HPN, with a synergistic effect between them. The older the patients, the higher the increase in Z-score during HPN.
Conclusion: HPN had no deleterious effect on cortical bone and actually improved trabecular bone in patients whose intestinal disease started after the age of 21 years.
Glucocorticoid Treatment of Ovariectomized Sheep Affects Mineral Density, Structure, and Mechanical Properties of Cancellous Bone
Authors: Schorlemmer Sandra , Gohl Christine , Iwabu Shohei , Ignatius Anita , Claes Lutz , Augat Peter 
Published: April 2006

Abstract
Thus far, orthopedic research lacks a suitable animal model of osteoporosis. In OVX sheep, 6 months of steroid exposure reduced bone density and mechanical competence. Bone properties and bone formation did not recover for another 6 months. Therefore, steroid-treated OVX sheep may serve as a large animal model for osteopenic bone.
Introduction: The purpose of this study was to explore the effects of glucocorticoid treatment on cancellous bone density, microarchitecture, biomechanics, and formation of new bone.
Materials and Methods: Sixteen ovariectomized merino sheep received either a 6-month glucocorticoid treatment (GLU; 0.45 mg/kg methylprednisolone) or were left untreated (control). Cancellous bone biopsy specimens from the tibia were harvested 6 months after ovariectomy. After 12 months, the animals were killed, and biopsy specimens were obtained from the contralateral tibia and the lumbar spine. All biopsy specimens were scanned for apparent bone mineral density by peripheral quantitative computed tomography (pQCT) and tested mechanically in uniaxial compression. Three-dimensional bone reconstructions were obtained by microcomputed tomography. Formation of new bone was analyzed using histologies of the femoral condyles.
Results: After 6 months, mineral density (−19%) and mechanical competence (−45%) were reduced by glucocorticoid treatment (p &lt; 0.1). BV/TV (−21%; p &lt; 0.01) and trabecular thickness (−20%; p = 0.01) declined, whereas BS/BV increased (24%; p = 0.01). After 12 months, mineral density (−33%) and mechanical properties (−55%) were reduced even more profoundly (p &lt; 0.05). Also, the structural parameters (BS/BV and Tb.Th.) still seemed to be affected by glucocorticoid treatment (p &lt; 0.05). New bone formation, assessed by measurement of osteoid surface, was markedly reduced (−63%, p &lt; 0.1) by glucocorticoid treatment. The differences between groups were generally more pronounced at the tibia and the femur than at the spine.
Conclusion: The effects of short-term high-dose steroid administration on bone mineral in this animal model were comparable with those observed in humans after long-term corticoid treatment. Reduction in bone quality and bone formation rate persisted after the cessation of steroid administration. Glucocorticoid treatment of ovariectomized sheep may therefore serve as a large animal model for steroid-induced osteopenia.
Enamel Structure Properties Controlled by Engineered Proteins in Transgenic Mice
Authors: Fong Hanson , White Shane N , Paine Michael L , Luo Wen , Snead Malcolm L , Sarikaya Mehmet 
Published: April 2006

Abstract
Amelogenin protein has regulatory effects on enamel biofabrication in mammalian tooth. Using teeth obtained from transgenic mice that express two separate protein-engineered versions of amelogenins, we made structure-nanomechanical properties correlations and showed 21% hardness and 24% elastic modulus degradation compared with the age-matched wildtype littermates. We attribute the inferior properties to the disorganization of the protein matrix resulting in defective mineral formation.
Introduction: Enamel is a bioceramic initiated by the biosynthesis of a complex mixture of proteins that undergoes self-assembly to produce a super molecular ensemble that controls the nucleation and habit of the crystalline mineral phase. Ultimately, the inorganic crystals grow to almost fully replace the organic phase. This biofabrication process occurs at physiologic conditions of pH, temperature, pressure, and ion concentration and results in the hardest tissue in the vertebrate body, with the largest and longest substituted-hydroxyapatite crystals known to biomineralizing systems. The most abundant protein of forming mammalian enamel, amelogenin, has been shown to have a significant regulatory effect on this complex process.
Materials and Methods: In this work, we present the effect of protein engineering of amelogenin on the mechanical properties of the resultant mouse enamel. We have produced two types of transgenic animals that express separate versions of amelogenin proteins that lack the required self-assembly domains. The resultant matured enamel was extensively characterized for its mechanical properties at the nanoscale by means of nanoindentation and atomic force microscopy (AFM). These techniques have enabled us to probe the mechanical properties that are representative of a single enamel rod.
Results: Our nanoindentation measurements have revealed that the altered amelogenin with dysfunctional self-assembly properties resulted in a degradation by as much as 21% in hardness and 24% in elastic modulus compared with the age-matched wildtype littermates. Furthermore, the enamel formed by these defective proteins is found to display a decrease in indentation surface pile-up volume by up to 32%.
Conclusions: We attribute these inferior mechanical properties for the enamel grown by the engineered amelogenins to result from the disorganization of the nanospheres formed in the protein matrix starting at the mineral nucleation stage with a consequential alteration to the fully grown mineral component. By engineering the properties of proteins that contribute to the nanoscale level of hierarchy in enamel biomineralization, it is possible to regulate the properties of the resulting bioceramic at the mesoscale level of the tissue.
Osteoclastogenesis, Bone Resorption, and Osteoclast-Based Therapeutics
Authors: Zaidi Mone , Blair Harry C , Moonga Baltit S , Abe Etsuko , Huang Christopher L-H 
Published: April 2006

Abstract
Over the past decade, advances in molecular tools, stem cell differentiation, osteoclast and osteoblast signaling mechanisms, and genetically manipulated mice models have resulted in major breakthroughs in understanding osteoclast biology. This review focuses on key advances in our understanding of molecular mechanisms underlying the formation, function, and survival of osteoclasts. These include key signals mediating osteoclast differentiation, including PU.1, RANK, CSF-1/c-fms, and src, and key specializations of the osteoclast including HCl secretion driven by H+-ATPase and the secretion of collagenolytic enzymes including cathepsin K and matrix metalloproteinases (MMPs). These pathways and highly expressed proteins provide targets for specific therapies to modify bone degradation. The main outstanding issues, basic and translational, will be considered in relation to the osteoclast as a target for antiresorptive therapies.
Marrow Cell Transplantation for Infantile Hypophosphatasia
Authors: Whyte Michael P , Kurtzberg Joanne , McALISTER William H , Mumm Steven , Podgornik Michelle N , Coburn Stephen P , Ryan Lawrence M , Miller Cindy R , Gottesman Gary S , Smith Alan K , Douville Judy , Waters-Pick Barbara , Armstrong R Douglas , Martin Paul L 
Published: April 2006

Abstract
An 8-month-old girl who seemed certain to die from the infantile form of hypophosphatasia, an inborn error of metabolism characterized by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP), underwent the first trial of bone marrow cell transplantation for this heritable type of rickets. After cytoreduction, she was given T-cell-depleted, haplo-identical marrow from her healthy sister. Chimerism in peripheral blood and bone marrow became 100% donor. Three months later, she was clinically improved, with considerable healing of rickets and generalized skeletal remineralization. However, 6 months post-transplantation, worsening skeletal disease recurred, with partial return of host hematopoiesis. At the age of 21 months, without additional chemotherapy or immunosuppressive treatment, she received a boost of donor marrow cells expanded ex vivo to enrich for stromal cells. Significant, prolonged clinical and radiographic improvement followed soon after. Nevertheless, biochemical features of hypophosphatasia have remained unchanged to date. Skeletal biopsy specimens were not performed. Now, at 6 years of age, she is intelligent and ambulatory but remains small. Among several hypotheses for our patient's survival and progress, the most plausible seems to be the transient and long-term engraftment of sufficient numbers of donor marrow mesenchymal cells, forming functional osteoblasts and perhaps chondrocytes, to ameliorate her skeletal disease.
In Vitro and In Vivo Synergistic Interactions Between the Runx2/Cbfa1 Transcription Factor and Bone Morphogenetic Protein-2 in Stimulating Osteoblast Differentiation
Authors: Yang Shuying , Wei Daoyan , Wang Dian , Phimphilai Mattabhorn , Krebsbach Paul H , Franceschi Renny T 
Published: April 2006

Abstract
Bone regeneration requires interactions between a number of factors including bone morphogenetic proteins (BMPs), growth factors, and transcriptional regulators such as Runx2/Cbfa1 (Runx2). Because each component may provide a unique contribution to the overall osteogenic response, we hypothesized that bone formation may be enhanced by using combinations of complimentary factors. As an initial test of this concept, interactions between BMP2 and Runx2 were examined using adenovirus-based expression vectors (AdCMV-Runx2, AdCMV-BMP2) in the pluripotent C3H10T1/2 cell line. Cells transduced with AdCMV-Runx2 strongly expressed osteoblast markers, such as alkaline phosphatase and osteocalcin, but formed only a weakly mineralized extracellular matrix in vitro, whereas cells transduced with AdCMV-BMP2 exhibited higher levels of mineralization, but only expressed low levels of Runx2 and osteocalcin mRNA. Significantly, when cells were transduced with optimal titers of both viruses, osteoblast differentiation was stimulated to levels that were 10-fold greater than those seen with either AdCMV-Runx2 or AdCMV-BMP2 alone. To measure in vivo osteogenic activity, virally transduced cells were subcutaneously implanted into immunodeficient mice. Cells transduced with control virus produced only fibrous tissue while those with AdCMV-Runx2 produced limited amounts of both cartilage and bone. In contrast, cells transduced with either AdCMV-BMP2 alone or AdCMV-BMP2 plus AdCMV-Cbfa1 generated large ossicles containing cartilage, bone, and a marrow cavity. However, ossification in the AdCMV-BMP2 plus AdCMV-Cbfa1 group was more extensive in that both mineral content and fractional bone area were greater than that seen in the AdCMV-BMP2 group. Thus, the increased osteoblast differentiation observed with combined adenovirus treatment in vitro is also manifested by increased bone formation in vivo. These results suggest that Runx2 and BMP2 have distinct, but complementary, roles in osteogenesis and that their combined actions may be necessary for optimal bone formation.