bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serial Changes in Bone Mineral Density and Bone Turnover After Correction of Secondary Hyperparathyroidism in a Patient with Pseudohypoparathyroidism Type Ib
Authors: Tollin Steven R. , Perlmutter Steven , Aloia John F. 
Published: April 2006

Abstract
Pseudohypoparathyroidism (PHP) is a disorder characterized by hypocalcemia and secondary hyperparathyroidism caused by primarily renal resistance to the effects of parathyroid hormone (PTH). However, as an indication of normal PTH responsiveness in bone, some patients with PHP develop skeletal disease because of longstanding secondary hyperparathyroidism. A patient is described with hypocalcemia, hyperphosphatemia, marked secondary hyperparathyroidism, and an increased alkaline phosphatase level. Subsequent evaluation revealed a diagnosis of PHP type Ib. The patient had radiographic evidence of skeletal disease caused by secondary hyperparathyroidism. A urinary level of N-telopeptide cross-links of type I collagen (NTX) was elevated markedly. Bone mineral density (BMD) was in the normal range at all measured sites, with BMD at the spine being higher than at the femur and distal radius. Treatment was initiated with calcium and calcitriol. Seven months later, calcium and PTH levels had normalized. The level of urinary NTX fell by 83%. Spinal BMD improved by 15%, and BMD at the femoral neck improved by 11%. Radial BMD was unchanged. This case emphasizes the importance of evaluating patients with PHP for hyperparathyroid bone disease and shows that correction of secondary hyperparathyroidism in patients with PHP can result in a significant suppression of previously accelerated bone turnover and to substantial gains in BMD at sites containing a major percentage of cancellous bone. The case also implies that assessment of bone turnover with urinary NTX and measurement of BMD with dual-energy X-ray absorptiometry (DEXA) may be useful in following the response of the skeleton to therapy in these patients and suggests the need for more studies of both NTX and BMD in patients with PHP.
Differential Expression Patterns of Runx2 Isoforms in Cranial Suture Morphogenesis
Authors: Park Mi-Hyun , Shin Hong-In , Choi Je-Yong , Nam Soon-Hyeun , Kim Young-Jin , Kim Hyun-Jung , Ryoo Hyun-Mo 
Published: April 2006

Abstract
Runx2 (previously known as Cbfa1/Pebp2αA/AML3), a key transcription factor in osteoblast differentiation, has at least two different isoforms using alternative promoters, which suggests that the isoforms might be expressed differentially. Haploinsufficiency of the Runx2 gene is associated with cleidocranial dysplasia (CCD), the main phenotype of which is inadequate development of calvaria. In spite of the biological relevance, Runx2 gene expression patterns in developing calvaria has not been explored previously, and toward this aim we developed three probes: pRunx2, which comprises the common coding sequence of Runx2 and hybridizes with all isoforms; pPebp2αA, which specifically hybridizes with the isoform transcribed with the proximal promoter; and pOsf2, which hybridizes with the isoform transcribed with the distal promoter. These probes were hybridized with tissue sections of mouse calvaria taken at various time points in development. Runx2 expression was localized to the critical area of cranial suture closure, being found in parietal bones, osteogenic fronts, and sutural mesenchyme. Pebp2αA and Osf2 showed tissue-specific expression patterns. The sites of Pebp2αA expression were almost identical to that of pRunx2 hybridization but expression was most intense in the sutural mesenchyme, where undifferentiated mesenchymal cells reside. The Osf2 isoform was strongly expressed in the osteogenic fronts, as well as in developing parietal bones, where osteopontin (OP) and osteocalcin (OC) also were expressed. However, in contrast to Pebp2αA, Osf2 expression did not occur in sutural mesenchyme. Pebp2αA also was expressed prominently in primordial cartilage that is found under the sutural mesenchyme and is not destined to be mineralized. Thus, Osf2 isoforms contribute to events later in osteoblast differentiation whereas the Pebp2αA isoform participates in a wide variety of cellular activities ranging from early stages of osteoblast differentiation to the final differentiation of osteoblasts.
Infrared Microscopic Imaging of Bone: Spatial Distribution of CO32−
Authors: Ou-Yang H. , Paschalis E. P. , Mayo W. E. , Boskey A. L. , Mendelsohn R. 
Published: April 2006

Abstract
This article describes a novel technology for quantitative determination of the spatial distribution of CO32− substitution in bone mineral using infrared (IR) imaging at ∼6 μm spatial resolution. This novel technology consists of an IR array detector of 64 × 64 elements mapped to a 400 μm × 400 μm spot at the focal plane of an IR microscope. During each scan, a complete IR spectrum is acquired from each element in the array. The variation of any IR parameter across the array may be mapped. In the current study, a linear relationship was observed between the band area or the peak height ratio of the CO32− v3 contour at 1415 cm−1 to the PO43− v1,v3 contour in a series of synthetic carbonated apatites. The correlation coefficient between the spectroscopically and analytically determined ratios (R2 = 0.989) attests to the practical utility of this IR area ratio for determination of bone CO32− levels. The relationship forms the basis for the determination of CO32− in tissue sections using IR imaging. In four images of trabecular bone the average CO32− levels were 5.95 wt% (2298 data points), 6.67% (2040 data points), 6.66% (1176 data points), and 6.73% (2256 data points) with an overall average of 6.38 ± 0.14% (7770 data points). The highest levels of CO32− were found at the edge of the trabeculae and immediately adjacent to the Haversian canal. Examination of parameters derived from the phosphate v1,v3 contour of the synthetic apatites revealed that the crystallinity/perfection of the hydroxyapatite (HA) crystals was diminished as CO32− levels increased. The methodology described will permit evaluation of the spatial distribution of CO32− levels in diseased and normal mineralized tissues.
Breast Cancer Cells Release Factors That Induce Apoptosis in Human Bone Marrow Stromal Cells
Authors: Fromigué Olivia , Kheddoumi Naïma , Lomri Abderrahim , Marie Pierre J. , Body Jean-Jacques 
Published: April 2006

Abstract
Breast cancer is associated frequently with skeletal metastases, which cause significant morbidity. The main mechanism is an increase in osteoclast-mediated bone resorption. We postulated that osteoblasts could be other essential target cells and previously showed that conditioned medium (CM) of breast cancer cells (BCCs) inhibits the proliferation of osteoblast-like cells. In this study, we investigated the effects of BCC-secreted products on osteoprogenitor cells using a clonal fetal human bone marrow stromal preosteoblastic cell line (FHSO-6) that expresses alkaline phosphatase (ALP) activity, type I collagen (COLI), and increased osteocalcin (OC) and osteopontin under treatment with dexamethasone (Dex), 1,25-dihydroxyvitamin D [1,25(OH)2D], or recombinant human bone morphogenetic protein 2 (rhBMP-2). Treatment with MCF-7 CM inhibited FHSO-6 cell survival in a dose-dependent and irreversible manner. Morphological investigation indicated that MCF-7 CM increased both apoptotic and necrotic cell number. MCF-7 CM increased caspases activity and a broad inhibitor of caspase activity (benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone [z-VAD-fmk]) partly reversed the CM-induced inhibition of FHSO-6 cell survival. Western blot analyses revealed an increased bax/bcl-2 ratio in MCF-7 CM-treated FHSO-6 cells. MCF-7 cells exhibit FasLigand as membrane-bound protein and as a soluble cytokine in the CM. Deprivation of MCF-7 CM from active FasLigand by saturation with a soluble Fas molecule suppressed the induction of FHSO-6 apoptosis, whereas fibroblast CM, which did not contain FasLigand, only weakly modified FHSO-6 cell survival because of increased cell necrosis. These data indicate that FasLigand secreted by BCCs induces apoptosis and necrosis of human preosteoblastic stromal cells through caspase cascade modulated by the bax and bcl-2 protein level. The induction of apoptosis in human bone marrow stromal cells by BCCs may contribute to the inappropriately low osteoblast reaction and bone formation during tumor-induced osteolysis in bone metastases.
Matrix Gla Protein in Xenopus laevis: Molecular Cloning, Tissue Distribution, and Evolutionary Considerations
Authors: Cancela M. L. , Ohresser M. C. P. , Reia J. P. , Viegas C. S. B. , Williamson M. K. , Price P. A. 
Published: April 2006

Abstract
Matrix Gla protein (MGP) belongs to the family of vitamin K-dependent, Gla-containing proteins and in higher vertebrates, is found in the extracellular matrix of mineralized tissues and soft tissues. MGP synthesis is highly regulated at the transcription and posttranscription levels and is now known to be involved in the regulation of extracellular matrix calcification and maintenance of cartilage and soft tissue integrity during growth and development. However, its mode of action at the molecular level remains unknown. Because there is a large degree of conservation between amino acid sequences of shark and human MGP, the function of MGP probably has been conserved throughout evolution. Given the complexity of the mammalian system, the study of MGP in a lower vertebrate might be advantageous to relate the onset of MGP expression with specific events during development. Toward this goal, MGP was purified from Xenopus long bones and its N-terminal amino acid sequence was determined and used to clone the Xenopus MGP complementary DNA (cDNA) by a mixture of reverse-transcription (RT)- and 5′- rapid amplification of cDNA ends (RACE)-polymerase chain reaction (PCR). MGP messenger RNA (mRNA) was present in all tissues analyzed although predominantly expressed in Xenopus bone and heart and its presence was detected early in development at the onset of chondrocranium development and long before the appearance of the first calcified structures and metamorphosis. These results show that in this system, as in mammals, MGP may be required to delay or prevent mineralization of cartilage and soft tissues during the early stages of development and indicate that Xenopus is an adequate model organism to further study MGP function during growth and development.
Validation of Peripheral Dual-Energy X-Ray Absorptiometry for the Measurement of Bone Mineral in Intact and Excised Long Bones of Rats
Authors: Nagy Tim R. , Prince Charles W. , Li Jing 
Published: April 2006

Abstract
We evaluated the precision and accuracy of peripheral dual-energy X-ray absorptiometry (DXA) for the measurement of bone mineral density (BMD) and bone mineral content (BMC) in intact and excised femurs and tibias from rats. Thirty-one Sprague-Dawley rats (18F/13M; 114–360 g) were used in the study. Precision and accuracy were determined in 23 rats and prediction equations were evaluated in an independent sample of 8 animals. Precision was determined by measuring the right hindquarter three times with repositioning between scans. The femur and tibia were then excised, cleaned, and scanned in triplicate, with repositioning. CVs ranged from 0.66 to 2.24%. Accuracy of BMC was determined by comparison to bone ash values. BMC values for the intact and excised femur significantly overestimated bone ash (p &lt; 0.001) by 33% and 5.5%, respectively. BMC for the intact tibia overestimated ash by 37% (p &lt; 0.001), whereas BMC for the excised tibia underestimated ash by 1% (p &lt; 0.05). However, BMC and bone ash were highly related for both bones, whether BMC was measured in the intact animal or after excision (r2 &gt; 0.99). Cross-validation of prediction equations in an independent sample showed that there were no significant differences between predicted ash (based on BMC from DXA) and measured bone ash. These results suggest the peripheral DXA is a useful tool for measuring intact and excised rat leg bones.
Bisphosphonate Therapy for Paget's Disease in a Patient with Hypoparathyroidism: Profound Hypocalcemia, Rapid Response, and Prolonged Remission
Authors: Stuckey B. G. A. , Lim E. M. , Kent G. N. , Ward L. C. , Gutteridge D. H. 
Published: April 2006

Abstract
Bisphosphonate treatment for severe Paget's disease leads to hypocalcemia followed by a secondary hyperparathyroid response to restore normocalcemia. A case is presented of a 60-year-old woman with polyostotic Paget's disease and postsurgical hypoparathyroidism. In 1993 her Paget's disease—alkaline phosphatase (ALP), 1260 U/liter (35–135 U/liter), and fasting urinary hydroxyproline excretion, 13.7 μmol/liter GF (0.4–1.9 μmol/liter)—was treated with intravenous pamidronate. Symptomatic hypocalcemia followed the first 60-mg dose, requiring large doses of calcium supplementation and calcitriol. Pamidronate therapy to a total dose of 360 mg was followed by rapid and prolonged remission with indices of bone turnover in the normal range within 2 months and persisting for at least 19 months after treatment. In 1999 relapse of Paget's disease—ALP, 511 U/liter (35–135 U/liter), and fasting urinary deoxypyridinoline/creatinine 53.1 μmol/mol (5–27 μmol/mol)—was treated with alendronate, 10 mg daily. Symptomatic hypocalcemia occurred again, requiring increased calcium and calcitriol therapy. Indices of bone turnover were within the normal range 9 weeks after the start of therapy. These responses were significantly more rapid and sustained than those observed in euparathyroid subjects. This case suggests that the lack of parathyroid response may modify the response to bisphosphonates by: (a) increasing intrinsic uptake of bisphosphonate into the pagetic skeleton, allowing response to a smaller dose; (b) increasing duration and severity of hypocalcemia after bisphosphonate therapy; and (c) removing the hyperparathyroid drive to reactivation of pagetic osteoclasts, leading to a prolonged remission. These observations have implications for optimizing bisphosphonate therapy both in Paget's disease and in osteoporosis.
Historical Vignette: Hypophosphatasia: Molecular Diagnosis of Rathbun's Original Case
Authors: Mumm Steven , Jones Jonathan , Finnegan Patrick , Whyte Michael P. 
Published: April 2006

Abstract
In 1948, Dr. John Campbell Rathbun characterized the disorder “hypophosphatasia” when he reported paradoxically low levels of alkaline phosphatase (ALP) activity in blood and in several tissues from an infant who died with rickets and epilepsy, which seemed to reflect “a new developmental anomaly.” Hypophosphatasia is now recognized to be an inborn error of metabolism featuring deficient activity of the tissue-nonspecific isoenzyme of ALP (TNSALP) caused by deactivating mutations in TNSALP. Here, we show, more than 50 years after Rathbun's case report, that analysis of the parental DNA indicates compound heterozygosity involving two missense mutations (G340A and A881C) in TNSALP caused the death of Rathbun's patient.
Alendronate in the Prevention of Bone Loss After a Fracture of the Lower Leg
Authors: Van Der Poest Clement E. , Van Engeland M. , Adèr H. , Roos J. C. , Patka P. , Lips P. 
Published: April 2006

Abstract
Fracture of a leg and the consequent absence from weight-bearing lead to local bone loss. A 1-year, single-center, prospective, randomized, double-blind study was conducted, to determine whether bone loss would occur in the proximal femur and the calcaneus after a fracture of the lower leg and whether this loss could be prevented by the antiresorptive drug bisphosphonate alendronate. Twenty-three men and 18 women with a recent unstable fracture of the lower leg were randomized to receive either 10 mg of alendronate daily or placebo. Bone mineral density (BMD) of both hips and the lumbar spine was measured at baseline and 6 weeks and 3, 6, and 12 months after start of the treatment. Quantitative ultrasound (QUS) measurements of the calcaneus were performed at baseline on the noninjured side and at 6 weeks and 3, 6, and 12 months after start of treatment on both sides. After 1 year, in the placebo group, there was a significant decrease from baseline in BMD of the hip on the side of the fracture. In the alendronate group, there was no significant change from baseline. The differences in BMD between the two treatment groups on the side of the fracture were significant in all sites of the hip: 4.4% (p = 0.016) in the trochanter, 4.6% (p = 0.016) in the femoral neck, and 3.9% (p = 0.009) in the total hip. In the hip on the contralateral side, there were no significant changes from baseline in either treatment group and there was no difference between the two treatment groups. BMD in the lumbar spine increased in the alendronate group, and after 1 year there was a significant difference between the active treatment and placebo group of 3.4% (p = 0.04). One year after fracture, ultrasound parameters of the calcaneus in the placebo group were significantly lower on the fractured side compared with the contralateral side (p &lt; 0.01). In the alendronate group, no significant difference between the two sides was observed. In conclusion, BMD of the proximal femur was still decreased 1 year after a fracture of the lower leg. Alendronate prevented this bone loss.
Quantitative Magnetic Resonance Imaging in the Calcaneus and Femur of Women With Varying Degrees of Osteopenia and Vertebral Deformity Status
Authors: Wehrli Felix W. , Hilaire Luna , Fernández-Seara Maria , Gomberg Bryon R. , Song Hee Kwon , Zemel Babette , Loh Louise , Snyder Peter J. 
Published: April 2006

Abstract
Quantitative magnetic resonance imaging (QMRI) allows measurement of two parameters that are related to the integrity of the trabecular bone: R2, the rate constant of the free induction signal, and trabecular bone volume fraction (BVF), the counterpart of apparent density. In this work, R2 and BVF were measured in 68 women (mean age, 58.2 ± 9.5 years) of varying spinal bone mineral density (BMD) T scores (mean, −1.37 ± 1.54) and vertebral fracture status on a commercial 1.5 T whole-body imager using customized image acquisition and processing techniques. Twenty-five of the patients had vertebral fractures, characterized by the total cumulative deformity burden exceeding 200%. R2 was measured in the calcaneus and proximal femur and BVF could be measured in the calcaneus only. On a pixel-by-pixel basis, calcaneal R2 and BVF within each subject were highly positively correlated (r2 = 0.61 ± 0.11) but the correlation of region-of-interest (ROI) means for different calcaneal sites among patients was weaker (r2 = 0.34; p &lt; 0.0001). The strongest discriminator of vertebral deformity was R2 of the calcaneus, which was lower in the fracture group, consistent with lower trabecular density. Among the calcaneal sites examined, the subtalar region, a location characterized by dense nearly horizontal trabeculae that transmit the stresses imparted by body weight from the tibia to the heel, best discriminated the two groups (p = 0.0001), with 77% diagnostic accuracy as determined from the area under the receiver operating characteristic (ROC) curve (compared with 66% for vertebral BMD). The cavum calcanei, an anterior site of low trabecular density, and the tuber calcanei (the location ordinarily used for ultrasound measurements) also had significantly reduced R2 in the fracture group (p &lt; 0.005 and p = 0.01, respectively). The R2av, computed as the average of all pixels in the calcaneus, was a strong discriminator as well (p &lt; 0.005). On the other hand, calcaneal BVF was only marginally discriminating (p = 0.05). Among the BMD sites examined, the lumbar spine (average L1-L4) was significant (p = 0.005, 66% diagnostic accuracy), as was the femoral neck (p = 0.01). The data suggest the calcaneus to be suited as a surrogate site to assess vertebral osteoporosis and that R2 is sensitive to alterations in bone quality not captured by density.
Cell Proliferation and Apoptosis During Fracture Healing
Authors: Li Gang , White Grainne , Connolly Chris , Marsh David 
Published: April 2006

Abstract
This study investigated the relation between cell proliferation and apoptosis during fracture healing in a mouse femoral fracture model. Left femoral osteotomies were performed in 30 mature male CFLP mice immobilized with uniplanar external fixators. Six animals were killed on days 2, 4, 8, 16, and 24 postfracture for examination. Localization of cell proliferation was examined using immunohistochemistry with proliferating cell nuclear antigen (PCNA) monoclonal antibody. Apoptotic cells were visualized with the terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end-labeling (TUNEL) method. Images of each time-specific specimen were captured. The total callus area, the positively labeled cells by PCNA, and TUNEL per high-power field were quantified. Cell proliferation and apoptosis were found coexisting during the entire period of study. In the early phases of fracture healing (days 2-8), PCNA-positive labeling was predominant and peaked at day 8 and the TUNEL-positive labeling was minimal. In later stages of fracture healing (days 16-24), PCNA expression declined at day 16 as callus ossification and remodeling spread within the fracture site and apoptosis was the dominant cell activity with the TUNEL-positive labeling peaking at day 16 and declining sharply at day 24. These cell activities were reflected by the change of fracture callus, where there was a continuous increase in total callus area to day 16 and subsequent decrease at day 24. This study indicated that cell proliferation and apoptosis are coupled events during fracture repair, cell proliferation is active at the early stages, and apoptosis is active during the phase of callus remodeling.
Anabolic Action of Parathyroid Hormone Is Skeletal Site Specific at the Tissue and Cellular Levels in Mice
Authors: Iida-Klein Akiko , Zhou Hua , Lu Shi Shou , Levine Lance R. , Ducayen-Knowles Mercedes , Dempster David W. , Nieves Jeri , Lindsay Robert 
Published: April 2006

Abstract
The cellular and molecular events triggering the anabolic response of the skeleton to exogenous parathyroid hormone (PTH) are not well understood. Despite the numerous bone mass studies in rats, few data are available for mice. Therefore, we treated 10-week-old female intact C57BL/6J mice with human PTH(1-34) delivered subcutaneously at a dose of 40 μg/kg per day 5 days a week for 3 weeks and 7 weeks. Bone mineral density (BMD) of total bone, femur, tibia, and lumbar vertebrae was measured weekly by PIXImus. Bone turnover was examined by histomorphometry, and gene expression of bone formation and resorption markers and osteoclastogenesis regulators in the excised femur and tibia was assessed by reverse-transcription polymerase chain reaction (RT-PCR) at 3 weeks and 7 weeks. The PTH-stimulated increase in BMD was more prominent in the tibia and femur than in the lumbar vertebrae, with an anabolic effect detected within 1-2 weeks and BMD continuing to increase. The appearance of a detectable PTH-stimulated increase in BMD was slower in the lumbar vertebrae where the increase was only significant after 7 weeks of treatment. Histomorphometric analysis of the proximal tibia at both 3 weeks and 7 weeks indicated significant time-dependent increases in trabecular area, trabecular number, trabecular and cortical widths, and osteoblast and osteoid perimeters. In the lumbar vertebrae, these stimulatory effects of PTH on trabecular area, trabecular number, and cortical width were smaller and not detected until 7 weeks. PTH-stimulated increases in bone turnover were evident by increased gene expression of osteocalcin (OC), tartrate-resistant acid phosphatase (TRAP), and receptor of activator nuclear factor κB (NF-κB) ligand (RANKL) in the tibia and femur. No significant difference in gene expression was observed between the two long bone sites. In conclusion, PTH exerts an anabolic action at the tissue and cellular levels in intact mice and the magnitude and temporal pattern of this anabolic action, as assessed by densitometry and histomorphometry, are skeletal site specific.