bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osteoporosis Prevalence and Levels of Treatment in Primary Care: The Australian BoneCare Study
Authors: Eisman John , Clapham Sharon , Kehoe Linda 
Published: April 2006

Abstract
The level of recognition and treatment of osteoporosis is not well characterized in primary care. In data from a large sample of postmenopausal women attending 927 primary care physicians, 29% of women reported one or more fractures after menopause. The great majority (72%) were not on any osteoporosis-specific therapy.
Introduction: Osteoporosis is often first recognized at the time of a low-trauma fracture. However, by this stage, the risk of subsequent fractures has already risen substantially. Moreover, in many countries, only a small proportion of women, who have already sustained fractures, receive a treatment shown to reduce this increased risk of further fractures.
Materials and Methods: This project was initiated to examine the prevalence of osteoporotic fractures, risk factors for osteoporosis, and use of antifracture therapy among postmenopausal Australian women. More than 88,000 women from 927 primary care physicians returned over 69,358 surveys. Of these, 57,088 reported the presence of a postmenopausal fracture or risk factors.
Results: Among these randomly selected postmenopausal women, 29% reported having had one or more low-trauma fractures after menopause (44% substantiated in current records). One-third of these women reported multiple fractures. The prevalence of all types of fractures, except rib and ankle, increased with age and low body weight. Those who reported fractures were also more likely to report early menopause, corticosteroid use, and a family history of osteoporosis. Moreover, those with vertebral fractures were more likely to record height loss, kyphosis, and back pain. Physical inactivity, low calcium intake, and smoking had no consistent relationship with any fracture outcome. Of the women who reported a fracture after menopause, only 28% were on any specific therapy for osteoporosis, and 7% were on calcium alone. Of those who had been told they had osteoporosis by a doctor, 40% were receiving specific osteoporosis therapy.
Conclusions: In this large study of postmenopausal Australian women attending primary care physicians, 29% reported at least one low-trauma fracture after menopause. Less than one-third of these women were on specific treatment for osteoporosis, and only 40% were ever told they had osteoporosis. Therefore, osteoporotic fractures are common in postmenopausal Australian women, and few, despite their substantially increased risk of further fractures, are on any specific anti-osteoporotic therapy. These data support the need for more effective education for the community and medical practitioners of the clinical significance of osteoporotic fractures and alternatives for treatment.
Strontium Ranelate Improves Bone Resistance by Increasing Bone Mass and Improving Architecture in Intact Female Rats
Authors: Ammann Patrick , Shen Victor , Robin Bruno , Mauras Yves , Bonjour Jean-Philippe , Rizzoli Rene 
Published: April 2006

Abstract
Strontium ranelate given to intact rats at doses up to 900 mg/kg/day increases bone resistance, cortical and trabecular bone volume, micro-architecture, bone mass, and total ALP activity, thus indicating a bone-forming activity and an improvement of overall bone tissue quality.
Introduction: Various anti-osteoporotic agents are available for clinical use; however, there is still a need for drugs able to positively influence the coupling between bone formation and bone resorption to increase bone mass and bone strength. Strontium ranelate (PROTELOS), a new chemical entity containing stable strontium (Sr), was tested for its capacity to influence bone quality and quantity.
Materials and Methods: The long-term effects of strontium ranelate on bone were investigated in intact female rats treated with various doses of strontium ranelate (0, 225, 450, and 900 mg/kg/day) for 2 years. In a second series of experiments, the effects of 625 mg/kg/day were evaluated in intact male and female rats for the same period of time. Bone mineral mass and mechanical properties were evaluated at various skeletal sites (vertebra and femur), and bone tissue micro-architecture was evaluated by static histomorphometry at the tibio-fibular junction (cortical bone) and at the tibia metaphysis (trabecular bone). Plasma total alkaline phosphatase (ALP) activity and serum levels of insulin-like growth factor-I (IGF-I) were also assessed.
Results: In female rats treated with strontium ranelate over 2 years, dose-dependent increases of bone strength and bone mass of the vertebral body (containing a large proportion of trabecular bone) and of the midshaft femur (containing mainly cortical bone) were detected without change in bone stiffness. Similar effects were observed in males at the level of the vertebra. This increase in mechanical properties was associated with improvements of the micro-architecture as assessed by increases of trabecular and cortical bone volumes and trabecular number and thickness. Finally, plasma total ALP activity and IGF-I were also increased in treated animals, compatible with a bone-forming activity of strontium ranelate.
Conclusion: A long-term treatment with strontium ranelate in intact rats is very safe for bone and improves bone resistance by increasing bone mass and improving architecture while maintaining bone stiffness.
The COMT val158met Polymorphism Is Associated With Peak BMD in Men
Authors: Lorentzon Mattias , Eriksson Anna-Lena , Mellström Dan , Ohlsson Claes 
Published: April 2006

Abstract
The associations between the functional val158met polymorphism of the estrogen-degrading COMT enzyme and skeletal properties in young men were investigated. BMD was associated with COMT genotype.
Introduction: Peak BMD is an important predictor of future risk of osteoporosis, and it is to a large extent determined by genetic factors. Estrogens are involved in the accretion of bone mass during puberty. Catechol-O-methyltransferase (COMT) is involved in the degradation of estrogens. There is a functional polymorphism in the COMT gene (val158met), resulting in a 60–75% difference in enzyme activity between the val (high activity [H]) and met (low activity [L]) variants. The aim of this cross-sectional study was to investigate the associations between this polymorphism and peak BMD in young men.
Materials and Methods: A total of 458 healthy men (mean age, 19 ± 0.6 years) were genotyped and classified as COMTLL, COMTHL, or COMTHH. Areal BMD (aBMD) was measured by DXA. Cortical and trabecular volumetric BMD (vBMD) were measured by pQCT. The associations between COMT genotype and skeletal phenotypes were determined.
Results and Conclusions: Regression models using physical activity, height, weight, age, and COMT genotype as covariates showed that COMT genotype was an independent predictor of aBMD in the total body and in all femur locations investigated, but not in the spine. The values for COMTHL and COMTHH were very similar, and therefore, they were pooled into one group. aBMD at Ward's triangle, trochanter, and total femur were 4.9%, 4.5%, and 3.7% lower, respectively, in the COMTLL than in the COMTHL/HH group (p &lt; 0.01). pQCT analyses showed that COMT genotype was an independent predictor of trabecular vBMD of the tibia, radius, and fibula. Trabecular vBMD of the radius and fibula in COMTLL was 5.3% and 7.4% lower, respectively, than that of the combined COMTHL/HH group. COMT genotype was associated with cortical vBMD but not with cortical cross-sectional area in the tibia. These findings show that the COMT polymorphism is associated with BMD in young adult men.
CCR1 Chemokines Promote the Chemotactic Recruitment, RANKL Development, and Motility of Osteoclasts and Are Induced by Inflammatory Cytokines in Osteoblasts
Authors: Yu Xuefeng , Huang Yuefang , Collin-Osdoby Patricia , Osdoby Philip 
Published: April 2006

Abstract
Chemoattractants that recruit OC precursors to locally inflamed sites of resorption are not well known. A chemokine receptor, CCR1, was expressed in OC precursors and elevated in mature OCs, and its ligands promoted OC precursor recruitment, RANKL development, and OC motility. Cytokines induced OB release of such chemokines, which may therefore significantly contribute to inflammatory bone loss.
Introduction: Chemokines, primarily of two major (CXC, CC) families, are essential signals for the trafficking and localization of circulating hematopoietic cells into tissues. However, little is known about their potential roles in osteoclast (OC) recruitment, development, or function. Previously, we analyzed CXC receptors in murine OC precursors and found high expression of CXCR4 that mediated their stromal-derived factor-1(SDF-1)-induced chemotaxis and collagen invasion. Here, we investigated if CC receptors and ligands, which are elevated in inflammatory and other osteolytic diseases, also play important roles in the recruitment, formation, or activity of murine bone-resorptive OCs.
Materials and Methods: CC chemokine receptor (CCR) mRNA expression was analyzed during OC formation induced by RANKL in murine RAW 264.7 cells and primary marrow cells. Corresponding CC chemokines were tested for their ability to elicit precursor chemotaxis or OC development, or to influence motility, bone resorption, adhesion, or survival in RANKL-differentiated OCs. Constitutive and inflammatory cytokine-induced release of the chemokines macrophage inflammatory protein-1α (MIP-1α) and regulated on activation, normal T-cell expressed and secreted (RANTES) was measured by ELISA for OCs, osteoblasts (OBs), and their precursor cells.
Results: CCR1 was expressed in murine marrow cells, the most prominent CCR in RAW cells, and upregulated by RANKL in marrow or RAW cells. Chemokines that bind CCR1 (MIP-1α, RANTES, and monocyte chemoattractant protein-3 [MCP-3]) were produced to varying degrees by murine OCs, OBs, and their precursors, and markedly increased by interleukin (IL)-1α and TNFα in differentiating OBs. RANTES, and especially MIP-1α, increased mature OC motility, but did not alter OC resorption activity, adhesion, or survival. All three chemokines stimulated chemotaxis of marrow or RAW cell precursors, leading to the greater formation of OCs (in number and size) after RANKL development of such chemoattracted marrow cells. All three chemokines also directly and dramatically enhanced OC formation in marrow cultures, through a pathway dependent on the presence of RANKL but without altering RANK expression.
Conclusions: Pathological increases in secretion of these chemokines from activated OBs or other cells may potently stimulate the chemotactic recruitment and RANKL formation of bone-resorptive OCs, thereby exacerbating local osteolysis in multiple skeletal diseases.
Amino-Terminal Parathyroid Hormone Fragment Analogs Containing α,α-di-alkyl Amino Acids at Positions 1 and 3
Authors: Shimizu Naoto , Dean Thomas , Khatri Ashok , Gardella Thomas J 
Published: April 2006

Abstract
To define and minimize the N-terminal PTH pharmacophore, the effects of introducing different conformationally constraining di-alkyl amino acids at positions 1 and 3 of PTH(1–14) analogs were studied. Improvements in PTH receptor-binding affinity and signaling potency were found, although some substitutions resulted in partial agonism.
Introduction: The N-terminal portion of parathyroid hormone (PTH) plays a critical role in PTH-1 receptor (P1R) activation. To investigate the mechanisms underlying this action and to minimize the N-terminal PTH pharmacophore, we employed the PTH(1–14) fragment as a scaffold for structure-activity relationship studies, and thus previously found that substitutions of the conformationally constraining, di-alkyl amino acid, α-amino-isobutyric acid (Aib), at positions 1 and 3 increase the P1R-binding affinity and signaling potency of the analog ∼100-fold. Here we extend these findings by investigating the effects of other constrained di-alkyl amino acids at positions 1 and/or 3 on PTH analog activity.
Materials and Methods: The di-alkyl amino acids, 1-aminocycloalkane-carboxylic acid (Acxc, x = 3, 5, or 6) or diethylglycine (Deg), representing alkyl configurations of varying volumes and shape (cyclic and linear), were introduced into the parent peptide, [M]PTH(1–14) (M = Ala1,3,12,Gln10,Har11,Trp14), and the analogs were tested for activity in P1R-expressing cells.
Results: Relative to the binding affinity and cAMP-stimulating potency of the parent peptide (IC50 = 27 mM; EC50 = 220 nM), PTH(1–14) analogs substituted at position 1 exhibited 2- (Ac3c) to 60-fold (Ac5c) increases in affinity and potency, as measured in LLC-PK1 cells stably expressing the cloned P1R. Combining the substitutions of Ac5c1 and Aib3 yielded the highest affinity and most potent PTH(1–14) and shorter-length analogs to date: [Ac5c1, Aib3,M]PTH(1-X) (X = 14, 11, and 10; IC50s = 80 nM, 260 nM, and 850 μM; EC50s = 1.7 nM, 3.1 nM, and 1.9 μM, respectively). The effects of Ac6c1 were similar to those of Ac5c1. A dissociation of binding affinity and signaling activity occurred with Deg, as [Deg1,3,M]PTH(1–14) was a partial agonist.
Conclusion: Constraining the N-terminal PTH backbone conformation with di-alkyl amino acids at positions 1 and 3 may be a general strategy for optimizing and minimizing the PTH pharmacophore; however, inhibitory side-chain effects may be encountered. The new analogs presented should be useful as minimum-length functional probes of the PTH-PTH receptor interaction mechanism.
Mineral Acquisition Rates in Developing Enamel on Maxillary and Mandibular Incisors of Rats and Mice: Implications to Extracellular Acid Loading as Apatite Crystals Mature
Authors: Smith Charles E , Chong Dennis Lee , Bartlett John D , Margolis Henry C 
Published: April 2006

Abstract
The formation rates of mineral in developing enamel were determined by microweighing of incisors of mice and rats. Computations indicated that a large excess of hydrogen ions would result from creating apatite at the calculated rates. Enamel organ cells (ameloblasts), therefore, likely excrete bicarbonate ions to prevent pH in fluid bathing enamel from becoming too acidic.
Introduction: Protons (H+) are generated whenever calcium and phosphate ions combine directly from aqueous solutions to form hydroxyapatite. Enamel is susceptible to potential acid loading during development because the amount of fluid bathing this tissue is small and its buffering capacity is low. The epithelial cells covering this tissue are also believed to form permeability barriers at times during the maturation stage when crystals grow at their fastest rates. The goal of this study was to measure the bulk weight of mineral present in rodent enamel at specific times in development and estimate the amount of acid potentially formed as the apatite crystals mature.
Materials and Methods: Upper and lower jaws of mice and rats were freeze-dried, and the enamel layers on the incisors were partitioned into a series of 0.5 mm (mouse) or 1.0 mm (rat) strips along the length of each tooth. The strips were weighed on a microbalance, ashed at 575°C for 18–24 h to remove organic material, and reweighed to determine the actual mineral weight for each strip.
Results and Conclusions: The data indicated that, despite differences in gross sizes and shapes of maxillary and mandibular incisors in rats and mice, the overall pattern and rates of mineral acquisition were remarkably similar. This included sharply increasing rates of mineral acquisition between the secretory and maturation stages, with peak levels approaching 40 μg/mm tooth length. Computer modeling indicated that quantities of H+ ions potentially generated as apatite crystals grew during the maturation stage greatly exceeded local buffering capacity of enamel fluid and matrix proteins. In other systems, bicarbonate ions are excreted to neutralize highly acidic materials generated extracellularly. Data from this study indicate that ameloblasts, and perhaps cells in other apatite-based hard tissues, use similar bicarbonate release mechanisms to control excess acid arising from mineral formation.
Males Have Larger Skeletal Size and Bone Mass Than Females, Despite Comparable Body Size
Authors: Nieves Jeri W , Formica Carmelo , Ruffing Jamie , Zion Marsha , Garrett Patricia , Lindsay Robert , Cosman Felicia 
Published: April 2006

Abstract
Gender differences in fractures may be related to body size, bone size, geometry, or density. We studied this in 18-year-old males (n = 36) and females (n = 36) matched for height and weight. Despite comparable body size, males have greater BMC and BMD at the hip and distal tibia and greater tibial cortical thickness. This may confer greater skeletal integrity in males.
Introduction: Gender differences in fractures may be related to body size, bone size, geometry, or density. We studied this in males (n = 36) and females (n = 36; mean age = 18 years) pair-matched for height and weight.
Materials and Methods: BMC, bone area (BA), and BMD were measured in the spine and hip using DXA. Distal tibia was measured by pQCT.
Results and Conclusions: Males had a higher lean mass (92%) compared with females (79%). No gender differences were observed for vertebral BMC or vertebral height, although males had greater width and thus BA at the spine. Males had greater BMC and BA at the femoral neck and total femur (p &lt; 0.02). Geometric variables of the hip including neck diameter and neck-axis length were also greater in males (p &lt; 0.02). There was greater cross-sectional moment of inertia, safety factor, and fall index in males (all p &lt; 0.02). Males had greater tibial BMC, volumetric BMD, and cortical area and thickness compared with females (p &lt; 0.01), with both greater periosteal circumference (p = 0.011) and smaller endosteal circumference (p = 0.058). Statistically controlling for lean mass reduced gender differences, but males still had 8% higher hip BMD (p = 0.24) and 5.3% higher total tibial BMD (p = 0.05). A subset of males and females were matched (n = 14 pairs) for total hip BA. Males in this subset still had greater BMC and BMD at the total hip (p &lt; 0.05) than females, despite similar BA. In summary, despite comparable body size, males have greater BMC and BMD than females at the hip and distal tibia but not at the spine. Differences in BMC and BMD were related to greater cortical thickness in the tibia. We conclude that differences in bone mass and geometry confer greater skeletal integrity in males, which may contribute to the lower incidence of stress and osteoporotic fractures in males.
Expression of LRP1 by Human Osteoblasts: A Mechanism for the Delivery of Lipoproteins and Vitamin K1 to Bone
Authors: Niemeier Andreas , Kassem Moustapha , Toedter Klaus , Wendt Dorte , Ruether Wolfgang , Beisiegel Ulrike , Heeren Joerg 
Published: April 2006

Abstract
Accumulating clinical and experimental data show the importance of dietary lipids and lipophilic vitamins, such as vitamin K1, for bone formation. The molecular mechanism of how they enter the osteoblast is unknown. Here we describe the expression of the multifunctional LRP1 by human osteoblasts in vitro and in vivo. We provide evidence that LRP1 plays an important role in the uptake of postprandial lipoproteins and vitamin K1 by human osteoblasts.
Introduction: Chylomicrons (CM) and their remnants (CR) represent the postprandial plasma carriers of dietary lipids. Dietary vitamin K1 is known to be transported in the circulation as part of CM/CR and is required by osteoblasts as an essential co-factor for the γ-carboxylation of bone matrix proteins. The molecular mechanisms underlying the delivery of lipophilic substances to bone are not understood. In this study, the expression and function of CM/CR receptors was examined in human osteoblasts.
Materials and Methods: Four human osteoblast-like cell lines were analyzed: two osteosarcoma lines (MG63, SaOS-2) and two telomerase-immortalized human bone marrow stromal cell lines (hMSC-TERT ‘4’ and ‘20’) after 1,25(OH)2vitamin D3 induction of osteoblastic differentiation (hMSC-TERT-OB). Receptor expression was examined by Western blotting and immunohistochemistry of normal human bone sections. Endocytotic receptor function was analyzed by cellular uptake assays using fluorescent and radiolabeled human CR. Vitamin K1-enriched CR (CR-K1) were generated in vivo after oral vitamin administration and vitamin K1 uptake by osteoblasts was measured by HPLC. The effect of CR-K1 uptake on osteocalcin carboxylation was measured by ELISA.
Results: Osteoblasts exhibit high levels of protein expression of the CR receptors LRP1 and LDLR. VLDLR is expressed to a lower degree. Immunohistochemistry of normal human bone sections showed strong LRP1 expression by osteoblasts and marrow stromal cells. Uptake of fluorescent CR by osteoblasts resulted in the typical pattern of receptor-mediated endocytosis. CR uptake was stimulated by the exogenous addition of the lipoprotein receptor ligands apolipoprotein E and lipoprotein lipase. Uptake was reduced by the known LRP1 inhibitors RAP, lactoferrin, and suramin, but not by LDL, which exclusively binds to the LDLR. Vitamin K1 uptake by hMSC-TERT-OB after incubation with CR-K1 was also shown to be sensitive to LPL stimulation and the LRP1 specific inhibitor lactoferrin. CR-K1 uptake into osteoblasts stimulated the γ-carboxylation of osteocalcin.
Conclusion: Human osteoblasts express receptors of the LDLR family with a capacity for vitamin K1 uptake through CR endocytosis, a novel mechanism for the delivery of dietary lipids and lipophilic vitamins to human bone. The current data suggest that, among the expressed receptors, LRP1 plays a predominant role.