bluuebunny/crossref_metadata_2025_split huggingface dataset:
Drugs Used to Treat Osteoporosis: The Critical Need for a Uniform Nomenclature Based on Their Action on Bone Remodeling
Authors: Riggs B Lawrence , Parfitt A Michael 
Published: April 2006

Abstract
There continues to be uncertainty about the classification of available drugs for treating osteoporosis. We find that grouping them into anti-catabolic and anabolic classes based on the mechanisms of their action on bone remodeling and fracture reduction removes ambiguities and provides a relatively straightforward classification.
The recent introduction of teriparatide into clinical practice initiated the era of anabolic therapy for osteoporosis, but it is still unclear how to define an anabolic drug. All drugs that increase bone mass do so by affecting bone remodeling. When their mechanisms of action on bone remodeling and on fracture reduction are considered, we find that anti-osteoporotic drugs fall naturally into either anti-catabolic or anabolic classes. Anti-catabolic drugs increase bone strength and reduce fractures mainly by decreasing the number of bone multicellular units (BMUs). This reduces perforative resorption and preserves skeletal microarchitecture (by preventing further structural damage to trabecular bone and increased porosity in cortical bone induced by high bone remodeling). Reduction in bone remodeling by anti-catabolic drugs may increase bone mass moderately during the interval in which previously initiated BMUs are completing mineralization. Some anti-catabolic drugs may also enhance the formation phase of the remodeling cycle, but their major action is to reduce overall bone turnover (i.e., the number of BMUs in bone). In contrast, anabolic drugs increase bone strength and reduce fractures by substantially increasing bone mass as a result of an overall increase in the number of BMUs combined with a positive BMU balance (the magnitude of the formation phase is greater than that of the resorption phase). Some anabolic drugs also induce renewed modeling, increase periosteal apposition and repair of trabecular microstructure. We hope that this classification will serve as a starting point for continued discussion on the important issue of nomenclature.
L-Arginine, the Natural Precursor of NO, Is Not Effective for Preventing Bone Loss in Postmenopausal Women
Authors: Baecker Natalie , Boese Andrea , Schoenau Eckhard , Gerzer Rupert , Heer Martina 
Published: April 2006

Abstract
NO is an important regulator of bone turnover. L-Arginine, the natural precursor of NO, can enhance NO production. However, no effect of L-arginine hydrochloride supplementation was found on bone metabolism or on BMD, bone mass, or bone structure of healthy postmenopausal women.
Introduction: Recent studies indicate that NO exerts an anabolic effect on bone cell activity. The NO level of the human body can be elevated by administering pharmacological NO donors. Animal studies and the first human trial showed that NO donor administration had a positive effect on bone formation and a negative effect on bone resorption. L-arginine, the natural precursor of NO, can enhance NO production. This study was conducted to examine the effect of an oral L-arginine supplement on bone metabolism of healthy postmenopausal women.
Materials and Methods: The participants in this study were 30 healthy, age-matched postmenopausal women, divided into two groups. For 6 months, one group (54.5 ± 4.1 years; 66.3 ± 10.5 kg) received a daily oral supplement with 18 g L-arginine hydrochloride (14.8 g free L-arginine). The other 15 volunteers (55.3 ± 4.4 years; 64.2 ± 9.1 kg) received 18 g dextrose as a placebo. To verify compliance, 24-h urinary excretion of nitrogen was analyzed for 2 consecutive days at baseline and after 2, 4, and 6 months. At baseline and after 2, 4, and 6 months of supplementation, blood was drawn for analysis of insulin-like growth factor-I (IGF-I) and biomarkers of bone metabolism. At baseline, after 6 months, and after 1 year, pQCT measurements were performed at trabecular and cortical sites of the radius and tibia. The two groups of subjects were compared by repeated measures ANOVA.
Results: As expected, in the group with L-arginine hydrochloride supplementation, nitrogen excretion rose, and in the placebo group, it remained constant. Only bone formation marker, procollagen type I propeptides (PICP), increased significantly (p &lt; 0.05) after 6 months of L-arginine supplementation. The results from pQCT showed no significant changes at any site in either group. No significant change in IGF-I concentration, which might have been caused by the L-arginine hydrochloride supplementation, was evident.
Conclusions: We conclude from these results that supplementation with L-arginine hydrochloride is not effective for improving bone mass in humans.
PGE2 Signal Through EP2 Promotes the Growth of Articular Chondrocytes
Authors: Aoyama Tomoki , Liang Bojian , Okamoto Takeshi , Matsusaki Takashi , Nishijo Koichi , Ishibe Tatsuya , Yasura Ko , Nagayama Satoshi , Nakayama Tomitaka , Nakamura Takashi , Toguchida Junya 
Published: April 2006

Abstract
EP2 was identified as the major PGE2 receptor expressed in articular cartilage. An EP2 agonist increased intracellular cAMP in articular chondrocytes, stimulating DNA synthesis in both monolayer and 3D cultures. Hence, the EP2 agonist may be a potent therapeutic agent for degenerative cartilage diseases.
Introduction: Prostaglandin E2 (PGE2) exhibits pleiotropic effects in various types of tissue through four types of receptors, EP1-4. We examined the expression of EPs and effects of agonists for each EP on articular chondrocytes.
Materials and Methods: The expression of each EP in articular chondrocytes was examined by immunohistochemistry and RT-PCR. A chondrocyte cell line, MMA2, was established from articular cartilage of p53−/− mice and used to analyze the effects of agonists for each EP. A search for molecules downstream of the PGE2 signal through the EP2 agonist was made by cDNA microarray analysis. The growth-promoting effect of the EP2 agonist on chondrocytes surrounded by cartilage matrix was examined in an organ culture of rat femora.
Results and Conclusion: EP2 was identified as the major EP expressed in articular cartilage. Treatment of MMA2 cells with specific agonists for each EP showed that only the EP2 agonist significantly increased intracellular cAMP levels in a dose-dependent manner. Gene expression profiling of MMA2 revealed a set of genes upregulated by the EP2 agonist, including several growth-promoting and apoptosis-protecting genes such as the cyclin D1, fibronectin, integrin α5, AP2α, and 14-3-3γ genes. The upregulation of these genes by the EP2 agonist was confirmed in human articular chondrocytes by quantitative mRNA analysis. On treatment with the EP2 agonist, human articular chondrocytes showed an increase in the incorporation of 5-bromo-2-deoxyuracil (BrdU), and the organ culture of rat femora showed an increase of proliferating cell nuclear antigen (PCNA) staining in articular chondrocytes surrounded by cartilage matrix, suggesting growth-promoting effects of the PGE2 signal through EP2 in articular cartilage. These results suggested that the PGE2 signal through EP2 enhances the growth of articular chondrocytes, and the EP2 agonist is a candidate for a new therapeutic compound for the treatment of degenerative cartilage diseases.
Azidothymidine Induces Apoptosis and Inhibits Cell Growth and Telomerase Activity of Human Parathyroid Cancer Cells in Culture
Authors: Falchetti Alberto , Franchi Alessandro , Bordi Cesare , Mavilia Carmelo , Masi Laura , Cioppi Federica , Recenti Raffaella , Picariello Lucia , Marini Francesca , Del Monte Francesca , Ghinoi Valentina , Martineti Valentina , Tanini Annalisa , Brandi Maria Luisa 
Published: April 2006

Abstract
Telomerase activity has been correlated to parathyroid carcinoma. Because its role in acquisition of a malignant phenotype by parathyroid cells is unclear, we treated telomerase-positive cultured human parathyroid cancer cells with the telomerase inhibitor AZT, evaluating cell telomerase activity, cytotoxic effects, growth, and morphological changes. In vitro exposure of these cells to AZT correlated with inhibition of cell proliferation.
Introduction: Parathyroid carcinoma represents an uncommon cause of primary hyperparathyroidism, whose spectrum of clinical presentation, degree of malignancy, and prognosis are difficult to be properly identified. Neck surgery, specifically an en bloc resection of primary tumor, is the only curative treatment. Alternatively, affected patients could undergo repetitive palliative surgical exeresis of metastatic nodules. It has been previously shown that telomerase activity is specifically present in parathyroid carcinoma cells, being absent in hyperplastic and adenomatous tissues. Thus, determination of telomerase activity could represent either a useful diagnostic molecular marker for human parathyroid carcinoma or a potential target for pharmacological intervention in a malignant neoplasia usually resistant to chemo- and radiotherapeutic interventions.
Materials and Methods: To further investigate the role of telomerase activity in acquisition of a malignant phenotype by parathyroid cells, we treated telomeric repeat amplification protocol-positive cultured human parathyroid cells with the telomerase inhibitor zidovudine, 3′-azido-3′deoxythymidine (AZT), evaluating cell telomerase activity, growth characteristics, potential cytotoxic effects, and morphological changes.
Results: Our findings indicate that in vitro exposure of human parathyroid cancer cells to AZT resulted in intracellular accumulation of AZT-monophosphate (AZT-MP) and inhibition of telomerase, which correlate with inhibition of human parathyroid cancer cell proliferation. Moreover, we also found that AZT induced an apoptotic rather than a necrotic type of cellular death. None of these effects were observed in human adenomatous parathyroid cells in culture.
Conclusions: Altogether these results indicate that AZT may be a highly effective agent against cancer parathyroid cells proliferation, which is an extremely important observation for a neoplasia which shows lack of response to classical pharmacological and physical antiblastic treatments.
Mechanotransduction in Bone Does Not Require a Functional Cyclooxygenase-2 (COX-2) Gene
Authors: Alam Imranul , Warden Stuart J , Robling Alexander G , Turner Charles H 
Published: April 2006

Abstract
COX-2 is a key enzyme involved in the response of bone to loading. However, using mice with a null mutation of the COX-2 gene, we found that a functional COX-2 gene is not required for mechanotransduction. This paradoxical finding may have resulted, in part, from mechanically induced COX-1 activity.
Introduction: Cyclooxygenase-2 (COX-2) is an important mediator in the response of bone to mechanical loading, with pharmacological inhibition of COX-2 effectively eliminating or reducing mechanically induced bone formation. In this study, we further investigated the role of COX-2 in skeletal mechanotransduction using a genetic approach. The aim was to compare the skeletal responsiveness of COX-2 homozygous mutant (COX-2−/−) and wildtype control (COX-2+/+) mice to investigate whether a functional COX-2 gene is necessary for mechanotransduction.
Materials and Methods: Adult female COX-2+/+ and COX-2−/− mice on a C57BL/6×129/ola background were studied using the ulna axial loading model. The response to 2 days of loading for 120 cycles/day at 2 Hz was measured histomorphometrically. Phenotypic characterization of the femurs in these mice was also performed. In a separate group of animals, the expression of the remaining COX isozyme, COX-1, was assessed using real-time RT-PCR 4 h after one bout of 120 loading cycles.
Results: Null mutation of the COX-2 gene resulted in a consistent femoral phenotype of reduced bone mass, altered architecture, and inferior mechanical properties. Many of these differences were nullified after adjustment for body weight. Nevertheless, body weight-corrected values showed a consistent trend of reduced mechanical properties in COX-2−/− mice. Genotype did not influence the response to mechanical loading, with no histomorphometric differences being found between COX-2+/+ and COX-2−/− mice. Real-time RT-PCR showed COX-2−/− mice to express significantly greater COX-1 expression in loaded ulnas than in loaded ulnas in COX-2+/+ mice. There were no differences in COX-1 expression in nonloaded ulnas.
Conclusions: A functional COX-2 gene was not found to be required for skeletal mechanotransduction. This is in contrast to previous pharmacological studies showing that COX-2 is critical to the response of bone to loading. Investigating a potential reason for the absence of a genotype difference in this study, we found that mice with a null mutation in the COX-2 gene possess inductive skeletal COX-1 expression.
Impaired Marrow Osteogenesis Is Associated With Reduced Endocortical Bone Formation but Does Not Impair Periosteal Bone Formation in Long Bones of SAMP6 Mice
Authors: Silva Matthew J , Brodt Michael D , Ko Mike , Abu-Amer Yousef 
Published: April 2006

Abstract
We used the SAMP6 osteoporotic mouse to examine the link between marrow osteogenic potential and in vivo cortical bone formation. SAMP6 marrow supported less in vitro osteogenesis than marrow from SAMR1 controls; SAMP6 mice had a corresponding deficit in endocortical mineralizing surface. This marrow/endocortical defect did not affect the periosteum, where SAMP6 mice had normal to enhanced bone formation.
Introduction: With aging, there may be a reduction in the number or proliferative capacity of bone marrow osteoprogenitors that may contribute to age-related decreases in bone formation. To examine the link between the ability of the marrow to support osteogenesis and age-related changes in bone formation, we measured in vitro and in vivo indices of osteogenesis in a model of osteoporosis, the senescence-accelerated mouse SAMP6.
Materials and Methods: Femora and tibias from SAMP6 and SAMR1 (control) mice were harvested at 2, 4, 6, and 12 months of age (168 bones total). Bone marrow cells were cultured under osteogenic conditions and stained for alkaline phosphatase (ALP) and alizarin red. Dynamic indices of bone formation were assessed histologically from calcein labels.
Results: ALP+ and alizarin red-positive areas were significantly less in cultures from SAMP6 bones versus SAMR1 (p &lt; 0.05), indicating less osteogenic potential. For example, SAMP6 tibial cultures had 21% less ALP+ area and 36% less alizarin red-positive area than SAMR1. Marrow from tibias had 2-fold greater osteogenesis than femoral marrow (p &lt; 0.001). SAMP6 mice had a deficit in endocortical mineralizing surface across all age groups (p &lt; 0.05), but no deficit in mineral apposition rate. Last, despite the marrow and endocortical deficits, SAMP6 mice had normal or slightly increased periosteal bone formation, consistent with their larger bone size.
Conclusion: SAMP6 bone marrow supports less in vitro osteogenesis than SAMR1, consistent with a lower concentration of marrow osteoprogenitors in SAMP6. SAMP6 mice have less endocortical mineralizing surface than SAMR1 at all ages but no detectable deficit in mineral apposition rate, which suggests a reduction in osteoblast number but normal function. Periosteal bone formation is unimpaired in SAMP6 mice, indicating that the marrow/endocortical defect does not affect the periosteal surface.
Overweight Postmenopausal Women Lose Bone With Moderate Weight Reduction and 1 g/day Calcium Intake
Authors: Riedt Claudia S , Cifuentes Mariana , Stahl Theodore , Chowdhury Hasina A , Schlussel Yvette , Shapses Sue A 
Published: April 2006

Abstract
Overweight postmenopausal women may be more susceptible to bone loss with weight reduction than previously studied obese women. The influence of energy restriction and Ca intake on BMD was assessed in 66 individuals. Weight reduction resulted in bone loss at several sites in women consuming 1 g Ca/day and was mitigated with higher calcium intake at 1.7 g/day.
Introduction: Bone loss is associated with weight loss in obese postmenopausal women and can be prevented with calcium (Ca) supplementation. However, because bone loss caused by weight loss may be greater in overweight than obese women, it is not clear whether Ca supplementation is also beneficial in overweight women.
Materials and Methods: We assessed the influence of caloric restriction at two levels of Ca intake on BMD and BMC in 66 overweight postmenopausal women (age, 61 ± 6 years; body mass index, 27.0 ± 1.8 kg/m2). Subjects completed either a 6-month energy-restricted diet (WL, n = 47) and lost 9.3 ± 3.9 % weight or maintained weight (WM; 1 g Ca/day, n = 19). Participants in the WL group were randomly assigned to either normal (1 g/day; WL NL-Ca) or high (1.7 g/day; WL Hi-Ca) Ca intake. Regional BMD and BMC were measured at baseline and after 6 months.
Results: During normal Ca intake, trochanter BMD and BMC and total spine BMD were decreased more in WL than WM women (p &lt; 0.05). The WL NL-Ca group lost more trochanter BMD (−4.2 ± 4.1%) and BMC (−4.8 ± 7.1%) than the WL Hi-Ca group (−1.4 ± 5.6% and −1.1 ± 8.1%, respectively; p &lt; 0.05). There were no significant changes in BMD or BMC at the femoral neck in any group. Weight loss correlated with trochanter BMD loss (r = 0.687, p &lt; 0.001) in the WL NL-Ca group.
Conclusion: Despite an intake of 1 g Ca/day, bone loss occurred at some sites because of weight loss. Calcium intake of 1.7 g/day will minimize bone loss during weight loss in postmenopausal overweight women.
Development and Initial Validation of a Risk Score for Predicting In‐Hospital and 1‐Year Mortality in Patients With Hip Fractures
Authors: Jiang Hong X , Majumdar Sumit R , Dick Donald A , Moreau Marc , Raso James , Otto David D , Johnston D William C 
Published: April 2006

AbstractOur objectives were to better define the rates and determinants of in‐hospital and 1‐year mortality after hip fracture. We studied a population‐based cohort of 3981 hip fracture patients. Using multivariable regression methods, we identified risk factors for mortality (older age, male sex, long‐term care residence, 10 prefracture co‐morbidities) and calculated a hip fracture‐specific score that could accurately predict or risk‐adjust in‐hospital and 1‐year mortality. Our methods, after further validation, may be useful for comparing outcomes across hospitals or regions.Introduction: Hip fractures in the elderly are common and associated with significant mortality and variations in outcome. The rates and determinants of mortality after hip fracture are not well defined. Our objectives were (1) to define the rate of in‐hospital and 1‐year mortality in hip fracture patients, (2) to describe co‐morbidities at the time of fracture, and (3) to develop and validate a multivariable risk‐adjustment model for mortality.Materials and Methods: We studied a population‐based cohort of 3981 hip fracture patients ≥60 years of age admitted to hospitals in a large Canadian health region from 1994 to 2000. We collected sociodemographic and prefracture co‐morbidity data. Main outcomes were in‐hospital and 1‐year mortality. We used multivariable regression methods to first derive a risk‐adjustment model for mortality in 2187 patients treated at one hospital and then validated it in 1794 patients treated at another hospital. These models were used to calculate a score that could predict or risk‐adjust in‐hospital and 1‐year mortality after hip fracture.Results and Conclusions: The median age of the cohort was 82 years, 71% were female, and 26% had more than four prefracture co‐morbidities. In‐hospital mortality was 6.3%; 10.2% for men and 4.7% for women (adjusted odds ratio, 1.8; 95% CI, 1.3‐2.4). Mortality at 1 year was 30.8%; 37.5% for men and 28.2% for women (adjusted p < 0.001). Older age, male sex, long‐term care residence, and 10 different co‐morbidities were independently associated with mortality. Risk‐adjustment models based on these variables had excellent accuracy for predicting mortality in‐hospital (c‐statistic = 0.82) and at 1 year (c‐statistic = 0.74). We conclude that 1 in 15 elderly patients with hip fracture will die during hospitalization, and almost one‐third of those who survive to discharge will die within the year. The determinants of mortality were primarily older age, male sex, and prefracture co‐morbidities. Our hip fracture‐specific risk‐adjustment tool is pragmatic and reliable, and after further validation, may be useful for comparing outcomes across different hospitals or regions.
Interobserver Reproducibility of Criteria for Vertebral Body Exclusion
Authors: Hansen Karen E , Binkley Neil , Christian Rose , Vallarta-Ast Nellie , Krueger Diane , Drezner Marc K , Blank Robert D 
Published: April 2006

Abstract
We studied reproducibility of the ISCD vertebral exclusion criteria among four interpreters. Surprisingly, agreement among interpreters was only moderate, because of differences in threshold for diagnosing focal structural defects and choice of which vertebra among a pair discordant for T-score, area, or BMC to exclude. Our results suggest that reproducibility may be improved by specifically addressing the sources of interobserver disagreement.
Introduction: Although DXA is widely used to measure vertebral BMD, its interpretation is subject to multiple confounders including osteoarthritis, aortic calcification, and scoliosis. In an attempt to standardize interpretation and minimize the impact of artifacts, the International Society for Clinical Densitometry (ISCD) established criteria for vertebral exclusion, including the presence of a focal structural defect (FSD), discrepancy of &gt;1 SD in T-score between adjacent vertebrae, and a lack of increase in BMC or area from L1 to L4. Whereas the efforts of the ISCD represent an important advance in BMD interpretation, the interobserver reproducibility with application of these criteria is unknown. We hypothesized that there would be substantial agreement among four interpreters regarding application of the exclusion criteria and the final lumbar spine T-score.
Materials and Methods: Each interpreter read a set of 200 lumbar DXA scans obtained on male veterans, applying the ISCD vertebral body exclusion criteria.
Results: Surprisingly, agreement among interpreters was only moderate. Differences in interpretation resulted from differing thresholds for recognition of FSD and the choice of excluding the upper or lower vertebral body for the criteria requiring comparison between adjacent vertebrae.
Conclusions: Despite their apparent simplicity, the ISCD vertebral exclusion criteria are difficult to apply consistently. In principle, appropriate refinement of the exclusion criteria may significantly improve interobserver agreement.