bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination Teriparatide and Raloxifene Therapy for Postmenopausal Osteoporosis: Results From a 6-Month Double-Blind Placebo-Controlled Trial
Authors: Deal Chad , Omizo Molly , Schwartz Elliott N , Eriksen Erik F , Cantor Per , Wang Jingyuan , Glass Emmett V , Myers Stephen L , Krege John H 
Published: April 2006

Abstract
We compared combination treatment with teriparatide plus raloxifene with teriparatide alone in women with postmenopausal osteoporosis in a 6-month double-blind, placebo-controlled trial that measured biochemical markers of bone turnover and BMD. Markers of bone formation and spine BMD increased similarly with teriparatide alone and combination therapy. However, combination therapy induced a significantly smaller increase in bone resorption versus teriparatide alone and significantly increased total hip BMD versus baseline.
Introduction: The effects of combining two approved treatments for osteoporosis with different modes of action were examined by comparing teriparatide [rhPTH(1–34)] monotherapy with combination teriparatide and raloxifene therapy.
Materials and Methods: A 6-month randomized, double-blind trial comparing teriparatide plus raloxifene (n = 69) versus teriparatide plus placebo (n = 68) was conducted in postmenopausal women with osteoporosis.
Results: Bone formation (N-terminal propeptide of type 1 collagen [PINP]) increased similarly in both treatment groups. However, the increase in bone resorption (serum C-terminal telopeptide of type I collagen [CTx]) in the combination group was significantly smaller than in the teriparatide-alone group (p = 0.015). Lumbar spine BMD significantly increased 5.19 ± 0.67% from baseline in the teriparatide-alone group. In the combination group, lumbar spine (6.19 ± 0.65%), femoral neck (2.23 ± 0.64%), and total hip (2.31 ± 0.56%) BMD significantly increased from baseline to study endpoint, and the increase in total hip BMD was significantly greater than in the teriparatide-alone group (p = 0.04). In the teriparatide-alone group, mean serum calcium levels increased from baseline to endpoint (0.30 ± 0.06 mg/dl, p &lt; 0.001), whereas mean serum phosphate remained unchanged. In the combination group, mean serum calcium was unchanged, and mean serum phosphate decreased (−0.20 ± 0.06 mg/dl, p &lt; 0.001) from baseline to endpoint. Changes in serum calcium (p &lt; 0.001) and phosphate (p &lt; 0.004) were significantly different between treatment groups. The safety profile of combination therapy was similar to teriparatide alone.
Conclusions: Combination therapy increased bone formation to a similar degree as teriparatide alone. However, the increase in bone resorption was significantly less and total hip BMD significantly increased for combination therapy compared with teriparatide alone. Combination treatment with raloxifene may thus enhance the bone forming effects of teriparatide. Further studies over longer treatment duration that include fracture endpoints are necessary to fully ascertain the clinical significance of combination raloxifene plus teriparatide therapy in postmenopausal osteoporosis.
Polymorphisms of the CLCN7 Gene Are Associated With BMD in Women
Authors: Pettersson Ulrika , Albagha Omar ME , Mirolo Max , Taranta Anna , Frattini Annalisa , McGuigan Fiona EA , Vezzoni Paolo , Teti Anna , Van Hul Wim , Reid David M , Villa Anna , Ralston Stuart H 
Published: April 2006

Abstract
Here we show that a common polymorphism causing a valine to methionine amino acid substitution at codon 418 (V418M) in the CLCN7 gene is associated with femoral neck BMD in women. Our study adds to accumulating evidence that shows that common allelic variants in monogenic bone disease genes often contribute to BMD regulation in normal subjects.
Introduction: The CLCN7 gene is a strong candidate for regulation of BMD, because mutations in CLCN7 cause some forms of osteopetrosis, a disease characterized by impaired osteoclast function and increased BMD. In this study, we sought to determine whether common allelic variation within CLCN7 was associated with BMD in the normal population.
Materials and Methods: We conducted mutation screening of the exons and intron-exon boundaries in CLCN7 by DNA sequencing in 50 normal subjects. We conducted an association study between common polymorphisms in CLCN7 and haplotypes defined by these polymorphisms and BMD values at the lumbar spine and femoral neck in a population-based cohort study of 1077 Scottish women 45–55 years of age.
Results: We identified 24 polymorphisms, but most were rare and only 4 had allele frequencies of &gt;5%. These were a conservative single nucleotide polymorphism (SNP) in exon 1 (rs3751884), a 50-bp tandem repeat polymorphism within intron 8, and two SNPs within exon 15 (rs12926089 and rs12926669), of which one (rs12926669) predicts an amino acid change from valine to methionine at codon 418 (V418M). The exon 15 SNPs were in strong linkage disequilibrium and were both associated with femoral neck BMD (p = 0.001–0.003). None of the other polymorphisms were associated with BMD, and long-range haplotypes showed a much weaker association with BMD than the exon 15 SNPs. The V418M polymorphism was an independent predictor of femoral neck BMD on multiple regression analysis accounting for 1% of the variance in BMD at this site.
Conclusions: Our study indicates that the V418M polymorphism of CLCN7 contributes to the genetic regulation of femoral neck BMD in women and adds to accumulating evidence that indicates that subtle polymorphic variation in genes that cause monogenic bone diseases also contribute to regulation of BMD in normal subjects.
Fibroblast Growth Factor-23 Is Regulated by 1α,25-Dihydroxyvitamin D
Authors: Collins Michael T , Lindsay John R , Jain Alka , Kelly Marilyn H , Cutler Carolee M , Weinstein Lee S , Liu Jie , Fedarko Neal S , Winer Karen K 
Published: April 2006

Abstract
Serum FGF-23 regulation was studied in patients with hypoparathyroidism or pseudohypoparathyroidism treated with calcitriol. Serum FGF-23 levels changed in parallel in response to changes in serum 1,25-D, suggesting that FGF-23 may be regulated by 1,25-D. In addition, the phosphaturic effect of FGF-23 may be diminished in the absence of PTH action on the kidney.
Introduction: Fibroblast growth factor (FGF)-23 is a recently described hormone that has been shown to be involved in the regulation of phosphate and vitamin D metabolism. The physiologic role of FGF-23 in mineral metabolism and how serum FGF-23 levels are regulated have yet to be elucidated. Three patients with mineral metabolism defects that allowed for the investigation of the regulation of FGF-23 were studied.
Materials and Methods: Patient 1 had postsurgical hypoparathyroidism and Munchausen's syndrome and consumed a pharmacologic dose of calcitriol. Patient 2 had postsurgical hypoparathyroidism and fibrous dysplasia of bone. She was treated with increasing doses of calcitriol followed by synthetic PTH(1–34). Patient 3 had pseudohypoparathyroidism type 1B and tertiary hyperparathyroidism. She underwent parathyroidectomy, which was followed by the development of hungry bone syndrome and hypocalcemia, requiring treatment with calcitriol. Serum FGF-23 and serum and urine levels of mineral metabolites were measured in all three patients.
Results: Patient 1 had an acute and marked increase in serum FGF-23 (70 to 670 RU/ml; normal range, 18–108 RU/ml) within 24 h in response to high-dose calcitriol administration. Patient 2 showed stepwise increases in serum FGF-23 from 117 to 824 RU/ml in response to increasing serum levels of 1α,25-dihydroxyvitamin D (1,25-D). Finally, before parathyroidectomy, while hypercalcemic, euphosphatemic, with low levels of 1,25-D (10 pg/ml; normal range, 22–67 pg/ml), and with very high serum PTH (863.7 pg/ml; normal range, 6.0–40.0 pg/ml), patient 3 had high serum FGF-23 levels (217 RU/ml). After surgery, while hypocalcemic, euphosphatemic, and with high serum levels of serum 1,25-D (140 pg/ml), FGF-23 levels were higher than preoperative levels (305 RU/ml). It seemed that the phosphaturic effect of FGF-23 was diminished in the absence of PTH or a PTH effect.
Conclusions: Serum FGF-23 may be regulated by serum 1,25-D, and its phosphaturic effect may be less in the absence of PTH.
A New Selective Estrogen Receptor Modulator, CHF 4227.01, Preserves Bone Mass and Microarchitecture in Ovariectomized Rats
Authors: Armamento-Villareal Reina , Sheikh Sharmin , Nawaz Abroo , Napoli Nicola , Mueller Cheryl , Halstead Linda R , Brodt Michael D , Silva Matthew J , Galbiati Elisabetta , Caruso Paola Lorenza , Civelli Maurizio , Civitelli Roberto 
Published: April 2006

Abstract
A new SERM, CHF 4227.01, given to 6-month-old female rats immediately after ovariectomy, preserved bone mass and bone microarchitecture without affecting uterus weight. It also decreased serum cholesterol and fat mass in estrogen-deficient rats.
Introduction: We tested the effect of a new benzopyran derivative, CHF 4227.01, with selective estrogen receptor modulator (SERM) activity on bone mass and biomechanics in ovariectomized (OVX) female rats in comparison with 17α-ethinylestradiol (EST), raloxifene (RLX), and lasofoxifene (LFX).
Materials and Methods: Four doses of CHF 4227.01 (0.001, 0.01, 0.1, and 1 mg/kg body weight [bw]/day) were administered in OVX animals daily by gavage 5 days/week for 4 months. EST was administered at a dose of 0.1 mg/kg bw/day, whereas RLX and LSX were administered at doses of 1 and 0.1 mg/kg bw/day, respectively, by gavage. In one group (Sham), rats were operated but the ovaries not removed; another OVX group was treated only with placebo.
Results and Conclusions: Treatment with CHF 4227.01 (1.0 and 0.1 mg/kg bw), EST (0.1 mg/kg bw), LFX (0.1 mg/kg bw), or RLX (1.0 mg/kg bw) prevented bone loss on the lumbar spine and the proximal femur assessed in vivo by DXA. Volumetric BMD obtained by pQCT ex vivo confirmed protection from bone loss in the spine and proximal femur among rats treated with CHF 4227.01. This effect was associated with strong inhibition of bone resorption both histologically and biochemically. Furthermore, CHF 4227.01 preserved trabecular microarchitecture, analyzed by μCT, and maintained biomechanical indices of bone strength in the spine and proximal femur, effects also observed for RLX, whereas LSX was less protective of microarchitecture. CHF 4227.01 treatment did not affect uterine weight, prevented the increase in body weight and fat mass seen in OVX animals, and decreased serum cholesterol to below the average of intact animals. In conclusion, CHF 4227.01 exhibits a promising therapeutic and safety profile as a new SERM on both skeletal and extraskeletal outcomes.
Influence of BMPs on the Formation of Osteoblastic Lesions in Metastatic Prostate Cancer
Authors: Feeley Brian T , Gamradt Seth C , Hsu Wellington K , Liu Nancy , Krenek Lucie , Robbins Paul , Huard Johnny , Lieberman Jay R 
Published: April 2006

Abstract
The purpose of this study was to evaluate the role of BMPs on the formation of metastatic prostate cancer lesions to bone. Our results show that BMPs influence the development and progression of osteoblastic lesions and suggest that therapies that inhibit BMP activity may reduce the formation and progression of osteoblastic lesions.
Introduction: Prostate adenocarcinoma is the leading cause of cancer in North American men. The formation of skeletal metastases affects ∼70% of patients with advanced disease, and a majority of these patients have osteoblastic lesions. Although BMPs have been found to be expressed in multiple oncogenic cell lines, their role in the formation of metastatic osteoblastic lesions remains uncharacterized. We hypothesized that BMPs influence the development of metastatic osteoblastic lesions associated with prostate cancer.
Materials and Methods: Western blot analysis and RT-PCR was used to determine BMP receptor expression on osteoblastic prostate cancer cell lines LAPC-4 and LAPC-9. Migration, invasion, and cellular proliferation assays were used to quantify the effects of BMP-2, −4, and −7 on LAPC-4 cells in vitro. LAPC-9 cells alone or transfected with a retrovirus overexpressing noggin were injected into the tibias of SCID mice, and the animals were followed for 8 weeks. Tumor size was determined by radiographs and direct measurement. Histology was performed at the time of death.
Results: We determined that BMP receptor mRNA and protein was expressed on osteoblastic prostate cancer cell lines LAPC-4 and LAPC-9. In vitro studies showed that BMP-2 and −7 stimulated cellular migration and invasion of prostate cancer cells in a dose-dependent fashion, although BMP-4 had no effect. Noggin inhibited cellular migration and invasion of BMP-2- and −7-stimulated LAPC-4 cells. LAPC-9 cells implanted into immunodeficient mouse tibias formed an osteoblastic lesion with sclerotic bone at 8 weeks. Formation of osteoblastic lesions was inhibited by overexpression of noggin by prostate cancer cells transduced with a retrovirus containing the cDNA for noggin.
Conclusions: BMPs are critical in the formation of the osteoblastic lesions associated with prostate cancer metastases, and future treatment strategies that inhibit local BMP activity may reduce the formation and progression of osteoblastic lesions.
Periosteal Progenitor Cell Fate in Segmental Cortical Bone Graft Transplantations: Implications for Functional Tissue Engineering
Authors: Zhang Xinping , Xie Chao , Lin Angela SP , Ito Hiromu , Awad Hani , Lieberman Jay R , Rubery Paul T , Schwarz Edward M , O'Keefe Regis J , Guldberg Robert E 
Published: April 2006

Abstract
A murine segmental femoral bone graft model was used to show the essential role of donor periosteal progenitor cells in bone graft healing. Transplantation of live bone graft harvested from Rosa 26A mice showed that ∼70% of osteogenesis on the graft was attributed to the expansion and differentiation of donor periosteal progenitor cells. Furthermore, engraftment of BMP-2-producing bone marrow stromal cells on nonvital allografts showed marked increases in cortical graft incorporation and neovascularization, suggesting that gene-enhanced, tissue engineered functional periosteum may improve allograft incorporation and repair.
Introduction: The loss of cellular activity in a structural bone allograft markedly reduces its healing potential compared with a live autograft. To further understand the cellular mechanisms for structural bone graft healing and repair and to devise a therapeutic strategy aimed at enhancing the performance of allograft, we established a segmental femoral structural bone graft model in mice that permits qualitative and quantitative analyses of graft healing and neovascularization.
Materials and Methods: Using this segmental femoral bone graft model, we transplanted live isografts harvested from Rosa 26A mice that constitutively express β-galactosidase into their wildtype control mice. In an attempt to emulate the osteogenic and angiogenic properties of periosteum, we applied a cell-based, adenovirus-mediated gene therapy approach to engraft BMP-2-producing bone marrow stromal cells onto devitalized allografts.
Results: X-gal staining for donor cells allowed monitoring the progression of periosteal progenitor cell fate and showed that 70% of osteogenesis was attributed to cellular proliferation and differentiation of donor progenitor cells on the surface of the live bone graft. Quantitative μCT analyses showed a 3-fold increase in new bone callus formation and a 6.8-fold increase in neovascularization for BMP-2/stromal cell-treated allograft compared with control acellular allografts. Histologic analyses showed the key features of autograft healing in the BMP-2/stromal cell-treated allografts, including the formation of a mineralized bone callus completely bridging the segmental defects, abundant neovascularization, and extensive resorption of bone graft.
Conclusions: The marked improvement of healing in these cellularized allografts suggests a clinical strategy for engineering a functional periosteum to improve the osteogenic and angiogenic properties of processed allografts.
Limited Rescue of Osteoclast-Poor Osteopetrosis After Successful Engraftment by Cord Blood From an Unrelated Donor
Authors: Nicholls Brian M , Bredius Robbert GM , Hamdy Neveen AT , Gerritsen Egbert JA , Lankester Arjan C , Hogendoorn Pancras CW , Nesbitt Stephen A , Horton Michael A , Flanagan Adrienne M 
Published: April 2006

Abstract
We report on a case of osteoclast-poor osteopetrosis who received a hematopoietic stem cell graft and, despite hematological engraftment, showed little signs of response in the skeletal defect. Clinical and laboratory studies supported the concept that the bone microenvironment remained abnormal, thus reducing the clinical response to transplantation.
Introduction: Osteopetrosis is a rare genetic disorder characterized by severely reduced bone resorption resulting from a defect in either osteoclast development (osteoclast-poor osteopetrosis) or activation (osteoclast-rich osteopetrosis). Patients with osteoclast-rich osteopetrosis can be rescued by allogenic hematopoietic stem cell transplantation; however, little information exists concerning the success of transplantation as a treatment for osteoclast-poor osteopetrosis. We report on a child with osteoclast-poor osteopetrosis whose diagnosis was delayed, consequently receiving a cord blood transplant from an unrelated donor at the age of 8 years. Engraftment was deemed successful by peripheral blood genotyping, although &gt;3 years after transplantation there was little rescue of the skeletal defect and anemia, and extramedullary hematopoiesis persisted.
Materials and Methods: Peripheral blood mononuclear cells from the osteopetrosis patient, before and after transplantation, were used to generate osteoclasts in vitro in the presence of macrophage colony-stimulating factor (M-CSF) and RANKL.
Results: Before transplantation few, small mononuclear osteoclasts formed (F-actin ring-positive cells, co-localizing with vitronectin receptor [αvβ3 integrin] and TRACP) associated with occasional, small resorption lacunae. Low levels of collagen C-terminal telopeptide (CTx) fragments were released from these cultures as assessed by ELISA (CrossLaps; patient, 12.85 nM; control, 448.6 nM). In contrast, osteoclasts formed in cultures after transplantation formed to a similar degree to control cultures from healthy individuals: large numbers of osteoclasts containing numerous nuclei were present, and approximately 50% of the surface of bone slices was resorbed, associated with intermediate levels of collagen fragment release (116.48 nM). The culture data reflect the histopathology and radiological findings and also support previous studies showing that neither M-CSF nor RANKL rescues osteoclast-poor osteopetrosis.
Conclusions: This is the first case reported in which a successful hematopoietic engraftment failed to correct an osteopetrotic skeletal defect, and this finding may be credited to the age at which the child was transplanted.
Dominant Negative N-Cadherin Inhibits Osteoclast Differentiation by Interfering With β-Catenin Regulation of RANKL, Independent of Cell-Cell Adhesion
Authors: Shin Chan Soo , Her Sun-Ju , Kim Jeong-Ah , Kim Do Hee , Kim Sang Wan , Kim Seong Yeon , Kim Hyo-Soo , Park Ki Ho , Kim Jung Gu , Kitazawa Riko , Cheng Su-Li , Civitelli Roberto 
Published: April 2006

Abstract
We studied the effects of dominant negative N-cadherin (NCadΔC) expression in ST2 cells on their ability to support osteoclastogenesis. Expression of NCadΔC in ST2 cells did not decrease cell-to-cell adhesion but significantly reduced osteoclast formation when co-cultured with BMMs. NCadΔC inhibited β-catenin/TCF signaling, resulting in decreased RANKL expression, which could contribute to the reduced osteoclast formation.
Introduction: Cadherin is a calcium-dependent cell adhesion molecule that plays major roles during embryonic development and morphogenesis. Classic cadherins interact with β-catenin, which is also involved in the Wnt signaling pathway. We tested whether disruption of N-cadherin function in stromal cells by dominant negative N-cadherin affects their ability to support osteoclastogenesis by altering heterotypic interaction with osteoclast precursors.
Materials and Methods: ST2 cells were transduced with retrovirus encoding extracellular domain-truncated, dominant negative N-cadherin (NCadΔC) and co-cultured with bone marrow macrophages (BMMs) to study the ability to support osteoclastogenesis. As a downstream target of NCadΔC, β-catenin/T-cell factor (TCF) transcriptional activity was analyzed using TOPflash reporter construct. Real-time RT-PCR analysis and RANKL-luciferase reporter assays were performed to study the effects of NCadΔC on the osteoprotegerin (OPG)/RANKL system.
Results: Immunoblotting analysis showed that primary bone marrow stromal cells, ST2 cells, and BMMs expressed N-cadherin. Retroviral expression of NCadΔC in ST2 cells did not significantly inhibit cell adhesion but markedly impaired the formation of TRACP+ osteoclasts (&gt;40%) when co-cultured with BMMs. However, the inhibition of osteoclastogenesis was not reproduced by neutralizing antibody against N-cadherin. Expression of NCadΔC, however, strongly suppressed β-catenin/TCF transcriptional activity in ST2 cells, which was rescued by constitutively active β-catenin adenovirus (Ad ΔN46 β-catenin) or constitutively active TCF mutant (pCS2-VP16ΔβXTCF-3). As a potential downstream target of Wnt signaling, we found that the expression of RANKL was reduced in ST2 cells expressing NCadΔC. Moreover, Wnt-3A, Ad ΔN46 β-catenin, and VP16ΔβXTCF-3 increased the expression of RANKL and enhanced the transcriptional activity of mouse RANKL promoter in ST2 cells.
Conclusions: Our data suggest that expression of dominant negative N-cadherin in ST2 cells suppressed osteoclastogenesis by interfering with β-catenin regulation of RANKL independent of cell-cell adhesion.