bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unmasking the Osteoinductive Effects of a G-Protein-Coupled Receptor (GPCR) Kinase (GRK) Inhibitor by Treatment With PTH(1–34)
Authors: Wang Liming , Quarles L Darryl , Spurney Robert F 
Published: April 2006

Abstract
The effects of GPCR systems in bone are regulated by a family of enzymes termed GRKs. We found that (1) GRK inhibition in osteoblasts has age-dependent effects on bone mass, and (2) the anabolic actions of GRK inhibition are revealed by treatment with PTH(1–34).
Introduction: The effects of G-protein-coupled receptor (GPCR) systems in bone are modulated by a family of enzymes termed GPCR kinases (GRKs). These enzymes directly phosphorylate GPCR substrate and desensitize receptor signaling. We previously found that expression of a GRK inhibitor in osteoblasts using transgenic (TG) technologies enhanced bone remodeling, and in turn, increased BMD in 6-week-old TG mice compared with non-TG littermate controls, presumably because of enhanced GPCR function. The aim of this study was to determine the age-dependent effects of the transgene.
Materials and Methods: BMD was monitored in TG mice and in controls at 6-week, 3-month, and 6-month time-points. To determine if the transgene enhanced responsiveness of bone to parathyroid hormone (PTH), we measured cyclic adenosine monophosphate (cAMP) generation by mouse calvaria ex vivo as well as the effects of treatment with PTH(1–34) on BMD, bone histomorphometry, and expression of the PTH-responsive gene RANKL in both TG mice and non-TG controls.
Results: Consistent with our previous findings, we found that BMD was increased in TG mice compared with controls at 6 weeks of age. The increase in BMD was most prominent in trabecular-rich lumbar spine and was not observed in cortical bone of the femoral shaft. In contrast to younger animals, however, BMD in older TG mice was not statistically different compared with non-TG mice at 3 months of age and was similar to non-TG animals at 6 months of age. The GRK inhibitor seemed to promote GPCR activation in older mice, however, because (1) PTH-induced cAMP generation by mouse calvaria ex vivo was enhanced in TG mice compared with controls, (2) GRK inhibition increased responsiveness of lumbar spine to the osteoinductive actions of PTH(1–34), and (3) the enhanced anabolic effect of PTH(1–34) was associated with increased expression of the PTH-responsive gene RANKL in calvaria of the TG animals. Bone histomorphometry confirmed that PTH(1–34) increased trabecular bone volume in TG mice and found that this increase in bone mass was caused by enhanced bone formation, predominantly as a result of an increase in the mineral apposition rate (MAR).
Conclusions: These data suggest that the anabolic effects of GRK inhibition are age dependent. The osteoinductive actions of the GRK inhibitor are, however, unmasked by treatment with PTH(1–34).
Safety and Efficacy of a Novel Salmon Calcitonin (sCT) Technology-Based Oral Formulation in Healthy Postmenopausal Women: Acute and 3-Month Effects on Biomarkers of Bone Turnover
Authors: Tankó László B , Bagger Yu Z , Alexandersen Peter , Devogelaer Jean-Pierre , Reginster Jean-Yves , Chick Rosalind , Olson Melvin , Benmammar Hakim , Mindeholm Linda , Azria Moise , Christiansen Claus 
Published: April 2006

Abstract
Oral administration of calcitonin could improve compliance to long-term treatment. Efficacy and safety of a novel oral formulation was assessed on 277 postmenopausal women. The results show (1) effective enteral absorption, (2) marked inhibition of bone resorption with minimal alteration of formation, and (3) reproducibility of responses over 3 months.
Introduction: We have recently introduced an Eligen technology-based oral formulation of salmon calcitonin (sCT) that effectively delivers the hormone to the circulation. The efficacy and safety during longer-term administration, however, has not been investigated in the target population.
Materials and Methods: This was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging clinical trial including 277 healthy postmenopausal women 55-85 years of age. Women received treatment with either daily (0.15, 0.4, 1.0, or 2.5 mg) or intermittent doses (1.0 mg, every other day) of sCT combined with the delivery agent (8-[N-2-hydroxi-5-chloro-benzoyl]-amino-caprylic acid, 200 mg) or placebo for 3 months. All participants received 1000 mg calcium plus 400 IU vitamin D daily throughout the study. Efficacy parameters were the acute and/or pre-dose changes in serum and urinary C-terminal telopeptide of type I collagen (CTx), N-mid osteocalcin (OC), bone-specific alkaline phosphatase (BSALP), calcium, and parathyroid hormone (PTH) measured by established immunoassays.
Results: After the first dose, sCT evoked dose-dependent decreases in serum CTx (−60.8% to −81.8% from baseline) compared with placebo, reaching nadirs 2-3 h after drug intake, after which, gradual increases were observed. The simultaneous acute changes in OC were statistically nonsignificant. Area under the curve (AUC) of serum CTx responses at months 1 and 3 showed strong correlation with those at baseline (both r = 0.78, p &lt; 0.001). At month 3, the placebo-corrected changes in the pre-dose value of serum and urinary CTx were significant only in the 1.0-mg dose group (−18.9% and −20.5%, respectively, p &lt; 0.05). The placebo-corrected change in OC was −8.6 (p = 0.09), whereas the change in BSALP was −7.3 (p = 0.02). The oral formulation was well tolerated, with mild to moderate gastrointestinal and skin manifestations apparent mainly in the high-dose groups.
Conclusion: The results of this 3-month trial show that the novel Eligen technology-based oral formulation of sCT has potential to become a safe and effective treatment for postmenopausal bone loss. Future trials are needed to assess the impact of long-term administration on changes in BMD and fracture risk.
Disc Space Narrowing Is Associated With an Increased Vertebral Fracture Risk in Postmenopausal Women: The OFELY Study
Authors: Sornay-Rendu Elisabeth , Munoz Françoise , Duboeuf François , Delmas Pierre D 
Published: April 2006

AbstractWe have analyzed the relationship between spine osteoarthritis and fractures in the OFELY cohort. Despite a higher BMD associated with spine OA, the risk of fragility fractures is not reduced. Disc space narrowing is associated with an increased risk of vertebral fracture. These data indicate that the risk of osteoporotic fracture should not be underestimated in women with spine OA.Introduction: Although osteoarthritis (OA) and osteoporosis both increase with age, their co-existence is uncommon. A higher BMD in OA is well documented, but a reduction of the fracture risk is still controversial. Our objective was to analyze the risk of fracture in postmenopausal women with spine OA.Materials and Methods: In a cross-sectional study, spine OA was evaluated by lateral radiographs according to the method of Lane, and BMD was measured by DXA in 559 postmenopausal women from the OFELY cohort (mean age, 68 ± 8 years; range, 58–94 years) 8 years after their inclusion into the study. Previous fragility fractures, all confirmed by radiographs, were prospectively registered during the annual follow-up for 8 years, and vertebral fractures were evaluated with spine radiographs. Severity of OA was assessed by scoring on osteophytes and disc narrowing on a four-point scale from 0 (normal) to 3 (severe) and graded as 0 (normal), 1 (mild osteophyte and/or narrowing), or 2 (moderate or severe osteophyte and/or narrowing).Results: Osteophytes and disc narrowing were present in 75% and 64%, respectively, of women at the lumbar spine and in 88% and 51%, respectively, at the thoracic spine, increasing with age. BMD of the spine, hip, and whole body increased with the severity of osteophytosis, whereas severity of narrowing was associated with a higher BMD only at the spine. Ninety-six fractures, including 48 vertebral fractures, occurred before OA assessment. No significant association was found between spine OA and all fragility fractures. In contrast, disc narrowing was associated with an increased risk of vertebral fracture with an odds ratio (95% CI) of 3.2 (1.1–9.3) after adjusting for age, body mass index, and BMD. The risk of vertebral fracture increased with the severity of disc narrowing. In comparison with the score 0, the odds ratio increased from 2.8 (0.9–8.7) to 4.6 (1.2–16.9) in women with mild to severe disc narrowing score.Conclusions: Despite a higher BMD, women with spine OA do not have a reduced risk of fracture. Disc narrowing is associated with a significant increased vertebral fracture risk.
Increased VEGF Expression in the Epiphyseal Cartilage After Ischemic Necrosis of the Capital Femoral Epiphysis
Authors: Kim Harry KW , Bian Haikuo , Randall Timothy , Garces Amanda , Gerstenfeld Louis C , Einhorn Thomas A 
Published: April 2006

Abstract
Ischemic injury to the immature femoral head produces epiphyseal cartilage damage and cessation of endochondral ossification. This study suggests that VEGF facilitates the repair of the necrotic epiphyseal cartilage, which is essential for restoration of endochondral ossification and re-establishment of the growth of the immature femoral head after ischemic necrosis.
Introduction: Legg-Calve-Perthes disease (LCPD) is a childhood form of osteonecrosis that produces growth arrest of the secondary center of ossification. The cessation of growth is caused by ischemic damage to the hypertrophic zone of the epiphyseal cartilage where endochondral ossification normally occurs. The role of vascular endothelial growth factor (VEGF) in restoring endochondral ossification in the epiphyseal cartilage after ischemic necrosis was investigated in a piglet model of LCPD because the resumption of normal growth is important for maintaining the spherical shape of the femoral head.
Materials and Methods: Piglet femoral heads were assessed 24 h to 8 weeks after the surgical induction of ischemia. Western blot analysis, ribonuclease protection assay (RPA), immunohistochemistry, and in situ hybridization were performed.
Results: Western blot analysis and RPA showed increased VEGF protein and mRNA expression, respectively, in the epiphyseal cartilage of the infarcted heads compared with the contralateral normal heads. In the normal femoral heads, VEGF-immunoreactivity (VEGF-IR) and transcripts were observed in the hypertrophic zone of the epiphyseal cartilage. In the infarcted heads, VEGF-IR and transcripts were no longer observed in the hypertrophic zone because of diffuse cell death in that zone from ischemia. However, VEGF-IR and transcripts were observed in the proliferative zone above the necrotic hypertrophic zone. At 8 weeks, vascular granulation tissue invasion of the necrotic hypertrophic zone was observed with active resorption of the necrotic cartilage. In some areas where the necrotic cartilage was completely resorbed, restoration of endochondral ossification was observed. In these areas, VEGF transcripts were observed in the newly formed hypertrophic zone.
Conclusions: VEGF expression was increased, and its spatial expression was altered in the epiphyseal cartilage after ischemic necrosis of the immature femoral head. VEGF upregulation in the proliferative zone after ischemic damage may play a role in stimulating vascular invasion and granulation tissue formation in the necrotic hypertrophic zone of the epiphyseal cartilage. This may be an important step toward facilitating the resorption of the necrotic cartilage and restoration of endochondral ossification leading to further growth and development of the femoral head.
Osteoporosis and Fracture Risk in Women of Different Ethnic Groups
Authors: Barrett-Connor Elizabeth , Siris Ethel S , Wehren Lois E , Miller Paul D , Abbott Thomas A , Berger Marc L , Santora Arthur C , Sherwood Louis M 
Published: April 2006

Abstract
Osteoporosis and 1-year fracture risk were studied in 197,848 postmenopausal American women from five ethnic groups. Weight explained differences in BMD, except among blacks, who had the highest BMD. One SD decrease in BMD predicted a 50% increased fracture risk in each group. Despite similar relative risks, absolute fracture rates differed.
Introduction: Most information about osteoporosis comes from studies of white women. This study describes the frequency of osteoporosis and the association between BMD and fracture in women from five ethnic groups.
Materials and Methods: This study was made up of a cohort of 197,848 community-dwelling postmenopausal women (7784 blacks, 1912 Asians, 6973 Hispanics, and 1708 Native Americans) from the United States, without known osteoporosis or a recent BMD test. Heel, forearm, or finger BMD was measured, and risk factor information was obtained; 82% were followed for 1 year for new fractures. BMD and fracture rates were compared, adjusting for differences in covariates.
Results: By age 80, more than one-fifth of women in each ethnic group had peripheral BMD T scores &lt;−2.5. Black women had the highest BMD; Asian women had the lowest. Only the BMD differences for blacks were not explained by differences in weight. After 1 year, 2414 new fractures of the spine, hip, forearm, wrist, or rib were reported. BMD at each site predicted fractures equally well within each ethnic group. After adjusting for BMD, weight, and other covariates, white and Hispanic women had the highest risk for fracture (relative risk ‘RR’ 1.0 ‘referent group’ and 0.95, 95% CI, 0.76, 1.20, respectively), followed by Native Americans (RR, 0.87; 95% CI, 0.57, 1.32), blacks (RR, 0.52; 95% CI, 0.38, 0.70), and Asian Americans (RR, 0.32; 95% CI, 0.15, 0.66). In age- and weight-adjusted models, each SD decrease in peripheral BMD predicted a 1.54 times increased risk of fracture in each ethnic group (95% CI, 1.48-1.61). Excluding wrist fractures, the most common fracture, did not materially change associations.
Conclusions: Ethnic differences in BMD are strongly influenced by body weight; fracture risk is strongly influenced by BMD in each group. Ethnic differences in absolute fracture risk remain, which may warrant ethnic-specific clinical recommendations.
Increased Bone Formation in Mice Lacking Apolipoprotein E
Authors: Schilling Arndt F , Schinke Thorsten , Münch Christian , Gebauer Matthias , Niemeier Andreas , Priemel Matthias , Streichert Thomas , Rueger Johannes M , Amling Michael 
Published: April 2006

Abstract
ApoE is a plasma protein that plays a major role in lipoprotein metabolism. Here we describe that ApoE expression is strongly induced on mineralization of primary osteoblast cultures. ApoE-deficient mice display an increased bone formation rate compared with wildtype controls, thereby showing that ApoE has a physiologic function in bone remodeling.
Introduction: Apolipoprotein E (ApoE) is a protein component of lipoproteins and facilitates their clearance from the circulation. This is confirmed by the phenotype of ApoE-deficient mice that have high plasma cholesterol levels and spontaneously develop atherosclerotic lesions. The bone phenotype of these mice has not been analyzed to date, although an association between certain ApoE alleles and BMD has been reported.
Materials and Methods: Primary osteoblasts were isolated from newborn mouse calvariae and mineralized ex vivo. A genome-wide expression analysis was performed during the course of differentiation using the Affymetrix gene chip system. Bones from ApoE-deficient mice and wildtype controls were analyzed using radiography, μCT imaging, and undecalcified histology. Cellular activities were assessed using dynamic histomorphometry and by measuring urinary collagen degradation products. Lipoprotein uptake assays were performed with125I-labeled triglyceride-rich lipoprotein-remnants (TRL-R) using primary osteoblasts from wildtype and ApoE-deficient mice. Serum concentrations of osteocalcin were determined by radioimmunoassay after hydroxyapatite chromatography.
Results: ApoE expression is strongly induced on mineralization of primary osteoblast cultures ex vivo. Mice lacking ApoE display a high bone mass phenotype that is caused by an increased bone formation rate, whereas bone resorption is not affected. This phenotype may be explained by a decreased uptake of triglyceride-rich lipoproteins by osteoblasts, resulting in elevated levels of undercarboxylated osteocalcin in the serum of ApoE-deficient mice.
Conclusion: The specific induction of ApoE gene expression during osteoblast differentiation along with the increased bone formation rate observed in ApoE-deficient mice shows that ApoE has a physiologic role as a regulator of osteoblast function.
Skeletal Localization and Neutralization of the SDF-1(CXCL12)/CXCR4 Axis Blocks Prostate Cancer Metastasis and Growth in Osseous Sites In Vivo
Authors: Sun Yan-Xi , Schneider Abraham , Jung Younghun , Wang Jianhua , Dai Jinlu , Wang Jingcheng , Cook Kevin , Osman Nadir I , Koh-Paige Amy J , Shim Hyusuk , Pienta Kenneth J , Keller Evan T , McCauley Laurie K , Taichman Russell S 
Published: April 2006

Abstract
To delineate the role of SDF-1 and CXCR4 in metastatic prostate cancer (CaP), positive correlations were established between SDF-1 levels and tumor metastasis. Neutralization of CXCR4 limited the number and the growth of intraosseous metastasis in vivo. Together, these in vivo metastasis data provide critical support that SDF-1/CXCR4 plays a role in skeletal metastasis.
Introduction: Previously we determined that the stromal-derived factor-1 (SDF-1)/CXCR4 chemokine axis is activated in prostate cancer (CaP) metastasis to bone. To delineate the role of SDF-1/CXCR4 in CaP, we evaluated SDF-1 levels in a variety of tissues and whether neutralization of SDF-1 prevented metastasis and/or intraosseous growth of CaPs.
Materials and Methods: SDF-1 levels were established in various mouse tissues by ELISA, immunohistochemistry, and in situ hybridization. To assess the role of SDF-1/CXCR4 in metastasis, bone metastases were established by administering CaP cells into the left cardiac ventricle of nude animals in the presence or absence of neutralizing CXCR4 antibody. The effect of SDF-1 on intraosseous growth of CaP cells was determined using intratibial injections and anti-CXCR4 antibodies and peptides.
Results: There was a positive correlation between the levels of SDF-1 and tissues in which metastatic CaP lesions were observed. SDF-1 levels were highest in the pelvis, tibia, femur, liver, and adrenal/kidneys compared with the lungs, tongue, and eye, suggesting a selective effect. SDF-1 staining was generally low or undetectable in the center of the marrow and in the diaphysis. SDF-1 mRNA was localized to the metaphysis of the long bones nearest to the growth plate where intense expression was observed near the endosteal surfaces covered by osteoblastic and lining cells. Antibody to CXCR4 significantly reduced the total metastatic load compared with IgG control-treated animals. Direct intratibial injection of tumor cells followed by neutralizing CXCR4 antibody or a specific peptide that blocks CXCR4 also decreased the size of the tumors compared with controls.
Conclusions: These data provide critical support for a role of SDF-1/CXCR4 in skeletal metastasis. Importantly, these data show that SDF-1/CXCR4 participate in localizing tumors to the bone marrow for prostate cancer.
Treatment of Painful Vertebral Fractures by Kyphoplasty in Patients With Primary Osteoporosis: A Prospective Nonrandomized Controlled Study
Authors: Kasperk Christian , Hillmeier Jochen , Nöldge Gerd , Grafe Ingo A , DaFonseca Katharina , Raupp Dorothea , Bardenheuer Hubert , Libicher Martin , Liegibel Ute Monika , Sommer Ulrike , Hilscher Ulrike , Pyerin Walter , Vetter Marcus , Meinzer Hans-Peter , Meeder Peter-Jürgen , Taylor Rod S , Nawroth Peter 
Published: April 2006

Abstract
This study investigates the effects of kyphoplasty on pain and mobility in patients with osteoporosis and painful vertebral fractures compared with conventional medical management.
Introduction: Pharmacological treatment of patients with primary osteoporosis does not prevent pain and impaired activity of patients with painful vertebral fractures. Therefore, we evaluated the clinical outcome after kyphoplasty in patients with vertebral fractures and associated chronic pain for &gt;12 months.
Materials and Methods: Sixty patients with primary osteoporosis and painful vertebral fractures presenting for &gt;12 months were included in this prospective, nonrandomized controlled study. Twenty-four hours before performing kyphoplasty, the patients self-determined their inclusion into the kyphoplasty or control group so that 40 patients were treated with kyphoplasty, whereas 20 served as controls. This study assessed changes in radiomorphology, pain visual analog scale (VAS) score, daily activities (European Vertebral Osteoporosis Study [EVOS] score), number of new vertebral fractures, and health care use. Outcomes were assessed before treatment and at 3 and 6 months of follow-up. All patients received standard medical treatment (1g calcium, 1000 IE vitamin D3, standard dose of oral aminobisphosphonate, pain medication, physical therapy).
Results: Kyphoplasty increased midline vertebral height of the treated vertebral bodies by 12.1%, whereas in the control group, vertebral height decreased by 8.2% (p = 0.001). Augmentation and internal stabilization by kyphoplasty resulted in a reduction of back pain. VAS pain scores improved in the kyphoplasty group from 26.2 ± 2 to 44.2 ± 3.3 (SD; p = 0.007) and in the control group from 33.6 ± 4.1 to 35.6 ± 4.1 (not significant), whereas the EVOS score increased in the kyphoplasty group from 43.8 ± 2.4 to 54.5 ± 2.7 (p = 0.031) and in the control group from 39.8 ± 4.5 to 43.8 ± 4.6 (not significant). The number of back pain-related doctor visits within the 6-month follow-up period decreased significantly after kyphoplasty compared with controls: mean of 3.3 visits/patient in the kyphoplasty group and a mean of 8.6 visits/patient in the control group (p = 0.0147).
Conclusions: The results of this study show significantly increased vertebral height, reduced pain, and improved mobility in patients after kyphoplasty. Kyphoplasty performed in appropriately selected osteoporotic patients with painful vertebral fractures is a promising addition to current medical treatment.