bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis
Authors: Dr. Garnero Patrick , Sornay-Rendu Elizabeth , Chapuy Marie-Claire , Delmas Pierre D. 
Published: February 2010

Abstract
Changes of bone turnover with aging are responsible for bone loss and play a major role in osteoporosis. Although an increase of bone turnover has been documented at the time of menopause, the subsequent abnormalities of bone resorption and formation and their potential role in determining bone mass in the elderly have not been investigated. To address this issue, we have measured a battery of new sensitive and specific markers of bone turnover in a population-based study of 653 healthy women analyzed cross-sectionally, including 432 women postmenopausal from 1 to 40 years, and the data were correlated with bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) at different skeletal sites. Bone formation was assessed by serum osteocalcin (OC), serum bone-specific alkaline phosphatase (B-ALP), serum C-propeptide of type I collagen (PICP), and bone resorption by the urinary excretion of two pyridinoline cross-linked peptides (NTX and CTX). Bone turnover increased in perimenopausal women with both irregular menses and elevated serum follicle stimulating hormone (FSH). Menopause induced a 37–52% and 79–97% increase in the bone formation and bone resorption marker levels, respectively (p &lt; 0.0001 except for PICP). In postmenopausal women, bone formation markers did not decrease with age. When resorption markers were corrected by whole body bone mineral content (BMC), the fraction of bone resorbed per day was not correlated with age in postmenopausal women and remained elevated for up to 40 years after menopause. In premenopausal women, the bone turnover rate accounted for only 0–10% of the variation in whole body BMC, total hip, distal radius, and lumbar spine BMD. With increasing time after menopause, the importance of the bone turnover rate as a determinant of bone mass increased at all sites and accounted for up to 52% of the BMD variance in elderly women. Thus, in women 20 years or more postmenopause, bone turnover was higher in those in the lowest quartile than in those in the highest quartile of BMD. In elderly women, 20 years since menopause and over, but not in younger ones, serum PTH was negatively correlated with serum 25-hydroxyvitamin D (r = −0.22,p &lt; 0.05) and explained only 5–8% of the bone turnover variance (p &lt; 0.01-0.001). These data indicate that the overall rates of both bone formation and bone resorption remain high in elderly women. The rate of bone turnover appears to play an increasing role as a determinant of bone mass with increasing time since menopause with a high bone turnover rate being associated with a low bone mass. Thus assessing bone marker levels may be useful in the evaluation of osteoporosis risk. In elderly women, secondary hyperparathyroidism caused in part by reduced serum 25-hydroxyvitamin D appears to be a marginal determinant of an increased bone turnover rate.
Calcitonin prevents bone loss but decreases osteoblastic activity in ovariohysterectomized beagle dogs
Authors: Monier-Faugere Marie-Claude , Geng Zhaopo , Qi Quanle , Arnala Illka , Malluche Hartmut H. 
Published: February 2010

AbstractThe antiresorptive effects of calcitonin are well documented. Recent in vitro and in vivo evidence points to an anabolic effect of calcitonin on osteoblasts. To assess the value of calcitonin in preventing the rapid and early bone loss after cessation of ovarian function and to investigate its effects on osteoblasts in vivo, 32 dogs were ovariohysterectomized (OHX) and 32 dogs were sham-operated (Sham). After the surgeries, half of the OHX and Sham dogs received every-other-day subcutaneous injections of human calcitonin (0.25 mg/dog/d), and the remaining dogs were given vehicle. Half of the animals had a bone biopsy at week 2 and were euthanized thereafter; the other half of the animals underwent a bone biopsy at month 1 and were euthanized at month 4. Blood drawings were done at baseline and at the time of each bone biopsy. Calcitonin prevented the increase in erosion depth seen in OHX animals and prevented the cancellous bone loss observed at 2 weeks and at 1 and 4 months. Calcitonin did not affect bone volume in Sham dogs. However, treatment with calcitonin induced a decrease in mineralizing surfaces and bone formation rates at the bone surface and cell level and an increase in mineralization lag time in both Sham and OHX animals without significantly affecting osteoblast number. This finding indicates that the negative effect of calcitonin on bone mineralization is not solely the result of a decrease in bone turnover. The data show that calcitonin, because of its antiresorptive effects, can prevent bone loss after cessation of ovarian function. However, short-term treatment with calcitonin does not stimulate osteoblast activity; on the contrary, it exerts a negative effect on osteoblastic bone formation and mineralization. Long-term studies are needed to investigate whether this unwanted effect of calcitonin on osteoblasts in vivo represents a transitory or persistent phenomenon.
The heritability of bone mineral density, ultrasound of the calcaneus and hip axis length: A study of postmenopausal twins
Authors: Arden N.K. , Baker J. , Hogg C. , Baan K. , Spector T.D. 
Published: February 2010

Abstract
Population based studies have demonstrated that having a first degree relative with a hip fracture is predictive of future hip fractures. Postmenopausal bone mineral density (BMD), ultrasound of calcaneus and hip axis length are associated with hip fracture, with the association for ultrasound and hip axis length being independent of BMD. The aim of this study was to determine the genetic component of these three important risk factors. We performed a classical twin study using 500 normal female twins, 128 identical and 122 non-identical pairs, aged 50 to 70 years. We measured bone mineral density at multiple sites, hip axis length (distance from the inner rim of the acetabulum to the greater trochanter), broadband ultrasound attenuation and velocity of sound of the calcaneus. Bone density had a strong genetic component at all sites with estimates of heritability ranging from 0.46 to 0.84. Hip axis length and velocity of sound had major genetic components with estimates of 0.62 and 0.61 respectively, which remained virtually unchanged after adjustment for bone mineral density. Broadband ultrasound attenuation had a moderate genetic component with an estimate of 0.53, which was reduced further to 0.45 after adjustment for BMD. In summary, all three bone measurements, which are independently associated with hip fracture, are independently heritable. This study suggests that a combination of different genetic factors acting on the structure, dimensions and density of bone may explain the importance of family history as a risk factor for hip fracture.
Age-related changes in osteogenic stem cells in mice
Authors: Bergman R.J. , Gazit D. , Kahn A.J. , Gruber H. , Mcdougall S. , Hahn T.J. 
Published: February 2010

Abstract
Osteoblasts arise from partially differentiated osteogenic progenitor cells (OPCs) which in turn arise from undifferentiated marrow stromal mesenchymal stem cells (MSCs). It has been postulated that age-related defects in osteoblast number and function may be due to quantitative and qualitative stem cell defects. To examine this possibility, we compared osteogenic stem cell number and in vitro function in marrow cells from 4-month-old and 24-month-old male BALB/c mice. Histologic studies demonstrated that these mice undergo age-related bone loss resembling that seen in humans. In primary MSC cultures grown in media supplemented with 10 nM dexamethasone, cultures from older animals yielded an average of 41% fewer OPC colonies per given number of marrow cells plated (p &lt; 0.001). This implies that for a given number of marrow cells there are fewer stem cells with osteogenic potential in older animals than there are in younger animals. The basal proliferative rate in cultures from older animals, as measured by 3H-thymidine uptake, was more than three times that observed in cultures from young animals (p &lt; 0.005). However, the increase in proliferative response to serum stimulation was 10-fold in the younger cultures (p &lt; 0.001) and insignificant (p &lt; 0.4) in the older cultures. Colonies in both age groups became alkaline phosphatase positive at the same rate, and virtually all colonies were positive after 12 days of culture. Cultures from both age groups produced abundant type I collagen. These studies suggest that defects in the number and proliferative potential of MSCs may underlie age-related defects in osteoblast number and function.
Bone quality factor analysis: A new noninvasive technique for the measurement of bone density and bone strength
Authors: Abbasi-Jahromi S. Hasan , Matayoshi Alicia , Kimble Robert , Dimarogonas Andrew , Pacifici Roberto 
Published: February 2010

Abstract
The sensitivity of bone mineral density (BMD) as a predictor of fracture risk is limited by the fact that this index does not take into account the geometrical and material characteristics of bone. In contrast, both BMD and bone architecture influence the quality factor (QF), the fraction of the inverse of the energy lost in one cycle of deformation. In this study we have compared the sensitivity of a QF analyzer and dual-energy X-ray absorptiometry (DXA) in detecting the changes induced by ovariectomy (OVX) on the QF, impact strength, and BMD of the femur of mature rats. QF and BMD were measured noninvasively before and 4 weeks after OVX or sham operation using a QF analyzer developed in our laboratory and a Hologic QDR 2000 bone densitometry, respectively. Impact strength was measured in excised femurs at the end of the study. The in vivo short-term precision (coefficient of variation) of the QF analyzer was 1.9%. BMD and QF measurements were highly correlated (r = 0.80, p &lt; 0.0001). At baseline, QF and BMD were similar in OVX and sham-operated rats. At 4 weeks, BMD was 14.7 + 0.9% lower than at baseline (p &lt; 0.001) in OVX rats and 5.3 + 1.3% lower in sham-operated rats (p &lt; 0.05). QF decreased 36.0 + 2.8% (p &lt; 0.0001) in OVX and 10.6 + 3.6% in sham rats (p &lt; 0.01). As a result, at 4 weeks the difference between sham-operated and OVX rats was larger (p &lt; 0.05) by QF than by BMD. Moreover, QF correlated better than BMD with impact strength and the difference in impact strength between sham and OVX mice was closer to that in QF than that in BMD. These data demonstrate that QF analysis is a precise technique that is more sensitive than DXA in detecting the changes in bone density and strength induced by OVX. QF analysis may represent a new, simple, and economic technique for predicting fracture risk.
Dual-energy X-ray absorptiometry derived structural geometry for stress fracture prediction in male U.S. marine corps recruits
Authors: Beck Thomas J. , Ruff Christopher B. , Mourtada Firas A. , Shaffer Richard A. , Maxwell-Williams Karen , Kao George L. , Sartoris David J. , Brodine Stephanie 
Published: February 2010

Abstract
A total of 626 U.S. male Marine Corps recruits underwent anthropometric measurements and dual-energy X-ray absorptiometry (DXA) scans of the femoral midshaft and the distal third of the tibia prior to a 12 week physical training program. Conventionally obtained frontal plane DXA scan data were used to measure the bone mineral density (BMD) as well as to derive the cross-sectional area, moment of inertia, section modulus, and bone width in the femur, tibia, and fibula. During training, 23 recruits (3.7%) presented with a total of 27 radiologically confirmed stress fractures in various locations in the lower extremity. After excluding 16 cases of shin splints, periostitis, and other stress reactions that did not meet fracture definition criteria, we compared anthropometric and bone structural geometry measurements between fracture cases and the remaining 587 normals. There was no significant difference in age (p = 0.8), femur length (p = 0.2), pelvic width (p = 0.08), and knee width at the femoral condyles (p = 0.06), but fracture cases were shorter (p = 0.01), lighter (p = 0.0006), and smaller in most anthropometric girth dimensions (p &lt; 0.04). Fracture case bone cross-sectional areas (p &lt; 0.001), moments of inertia (p &lt; 0.001), section moduli (p &lt; 0.001), and widths (p &lt; 0.001) as well as BMD (p &lt; 0.03) were significantly smaller in the tibia and femur. After correcting for body weight differences, the tibia cross-sectional area (p = 0.03), section modulus (p = 0.05), and width (p = 0.03) remained significantly smaller in fracture subjects. We conclude that both small body weight and small diaphyseal dimensions relative to body weight are factors predisposing to the development of stress fractures in this population. These results suggest that bone structural geometry measurements derived from DXA data may provide a simple noninvasive methodology for assessing the risk of stress fracture.
Calbindin-D9k and calbindin-D28k expression in rat mineralized tissues in vivo
Authors: Berdal A. , Hotton D. , Saffar J.L. , Thomasset M. , Nanci A. 
Published: February 2010

Abstract
Following their terminal differentiation, highly specialized cells, ameloblasts, odontoblasts, and osteoblasts sequentially elaborate mineralized tissues. While the developmental expression pattern of matrix proteins has been studied extensively, less attention has been paid to the molecules involved in calcium handling, such as calcium-binding proteins. This shortcoming, as well as previous conflicting data, led us to conduct studies on calbindin-D9k and calbindin-D28k in rat mandibular bone and incisor based on several methods established on rat ameloblasts in vivo. Radioimmunoassays showed that calbindin-D28k accounts for approximately 0.1% of cytosolic proteins in the ectomesenchymal fraction and 1% in the epithelial fraction of the rat incisor and is 100-fold more concentrated than calbindin-D9k in both tissue types. Western blot analysis confirmed that the anticalbindin-D28k reactive species corresponded to the well characterized renal calbindin-D28k in the ectomesenchyme. In this tissue, calbindin-D28k was ultrastructurally immunolocalized in the odontoblasts. Quantitative immunocytochemistry showed that labeling was distributed throughout their nucleus and cytoplasm. The similar cytoplasmic distribution of both calbindin-D proteins and mRNAs suggests that their expression is regulated at the subcellular level. In particular, immunoreactive calbindin-D28k appeared to be associated with rough endoplasmic reticulum. Calbindin-D9k antisense probe showed negligible labeling in odontoblasts, in parallel with the protein quantities measured (∼10 ng/mg of total protein). Finally, in situ hybridization showed transcripts for both calbindins-D in ameloblasts and also in osteoblasts. In summary, the present results support the concept that an elevated expression of these vitamin D–dependent calcium-binding proteins may characterize the phenotype of cells directly involved in the elaboration of mineralized tissues, enamel, dentine, and bone.
Changes in biological activity of bone cells in ovariectomized rats revealed by in situ hybridization
Authors: Ikeda Tohru , Yamaguchi Akira , Yokose Satoshi , Nagai Yumiko , Yamato Hideyuki , Nakamura Toshitaka , Tsurukami Hiroshi , Tanizawa Tatsuhiko , Yoshiki Shusaku 
Published: February 2010

Abstract
Twelve-week-old female rats were ovariectomized (OVX) and compared with sham-operated control rats at 3, 5, 7, 10, 14, 30, and 60 days postoperation with respect to the expression of type I collagen and osteopontin mRNAs, as well as bone structure and the number of osteoclasts. The trabecular number and separation were significantly decreased and increased, respectively, in the metaphyseal trabecular bones of OVX rat femurs. The number of osteoclasts was significantly increased in the same region of OVX rats at 3 and 5 days postoperation. Type I collagen mRNA was expressed in osteoblasts, and osteopontin mRNA was expressed in some osteoclasts, in mononuclear cells on the bone resorption surface, and in osteocytes near the resorption surface. In the metaphyseal trabecular bone, type I collagen and osteopontin mRNA expression levels in individual cells was initially increased in OVX rats from 7 to 10 days postoperation, and this was sustained for 60 days. The number of osteopontin mRNA-expressing osteocytes was also significantly increased at 10 days postoperation, which lasted until 60 days. In the epiphysis, an increase in type I collagen mRNA expression was initially observed in OVX rats at 14 days postoperation, which lasted until 60 days. The number of osteopontin mRNA-expressing osteocytes was virtually identical until 30 days postoperation in the epiphysis. These findings indicated that the biological activities of osteoblasts and osteocytes are stimulated in bones of the OVX rat and that the response for OVX differs between the metaphysis and epiphysis. Furthermore, the number of osteopontin mRNA-expressing osteocytes was increased only in bones that tended to be resorbed after OVX. This indicates that some osteocytes were stimulated to express osteopontin mRNA by estrogen deficiency and suggests that these osteopontin mRNA-expressing osteocytes may be involved in regulation of bone metabolism.
Differential regulation of receptor-stimulated cyclic adenosine monophosphate production by polyvalent cations in MC3T3-E1 osteoblasts
Authors: Hartle James E. , Prpic Veronica , Siddhanti Suresh R. , Spurney Robert F. , Quarles L. Darryl 
Published: February 2010

Abstract
Extracellular cations have paradoxical trophic and toxic effects on osteoblast function. In an effort to explain these divergent actions, we investigated in MC3T3-E1 osteoblasts if polyvalent cations differentially modulate the agonist-stimulated cyclic adenosine monophosphate (cAMP) pathway, an important regulator of osteoblastic function. We found that a panel of cations, including gadolinium, aluminum, calcium, and neomycin, inhibited prostaglandin E1 (PGE)-stimulated cAMP accumulation but paradoxically potentiated parathyroid hormone (PTH)-stimulated cAMP production. In contrast, these cations had no effect on forskolin- or cholera toxin–induced increases in cAMP, suggesting actions proximal to adenylate cyclase and possible modulation of receptor interactions with G proteins. Phorbol 12-myristate 13-acetated (PMA) mimicked the effects of cations on PGE1-and PTH-stimulated cAMP accumulation in MC3T3-E1 cells, respectively, diminishing and augmenting the responses. Moreover, down-regulation of protein kinase C (PKC) by overnight treatment with PMA prevented gadolinium (Gd3+) from attenuating PGE1- and enhancing PTH-stimulated cAMP production, indicating involvement of PKC-dependent pathways. Cations, however, activated signal transduction pathways not coupled to phosphatidylinositol-specific phospholipase C (PI-PLC), since there was no corresponding increase in inositol phosphate formation or intracellular calcium concentrations. In addition, pertussis toxin treatment failed to prevent Gd3+-mediated suppression of PGE1-Stimulated cAMP, suggesting actions independent of Gαi. Thus, polyvalent cations may either stimulate or inhibit hormone-mediated cAMP accumulation in osteoblasts. These differential actions provide a potential explanation for the paradoxical trophic and toxic effects of cations on osteoblast function that occur in vivo under different hormonal conditions.
β-Adrenergic receptor kinase-like activity and β-arrestin are expressed in osteoblastic cells
Authors: Bliziotes Michael , Murtagh James , Wiren Kristine 
Published: February 2010

Abstract
Biologic responses to peptide calciotropic hormones, such as parathyroid hormone (PTH) and calcitonin, exhibit desensitization. As with most hormones, however, the mechanisms of desensitization are not completely understood. For the β2-adrenergic receptor (β2AR) system, which is coupled to adenylyl cyclase via the stimulatory guanine nucleotide-binding regulatory (Gs) protein, homologous desensitization is mediated in part by a receptor-specific kinase (βARK) and a soluble cofactor (β-arrestin). Recently, this system has been reported to be involved in rapid homologous desensitization of the PTH/parathyroid hormone receptor protein (PTHrP) receptor. We have identified the presence of this system in bone using reverse-transcriptase PCR. Nucleotide sequence of PCR fragments from ROS 17/2.8 cells revealed 100% identity with rat brain βARK1 and β-arrestin 1 sequences. Northern analyses with RNA from ROS 17/2.8, UMR 106-H5 cells, and primary cultures of nontransformed neonatal rat calvariae demonstrated two mRNA species of 4 and 2.6 kilobases (kb) for βARK and 7.5 kb for β-arrestin, comparable to those found in bovine brain. βARK-like activity was demonstrated in cytosolic extracts of the UMR 106-H5 cells by assessing phosphorylation of the retinal photoreceptor, rhodopsin, by the extracts. Phosphorylation was enhanced with light-activated rhodopsin and by bovine brain Gβγ subunits; heparin inhibited phosphorylation. These findings are characteristic of βARK. Expression of β-arrestin in the UMR 106-H5 cells was confirmed by immunoblot. Thus, osteoblastic cells express proteins, βARK, and β-arrestin, which may regulate desensitization of calciotropic hormone receptors.
A controlled trial of raloxifene (LY139481) HCl: Impact on bone turnover and serum lipid profile in healthy postmenopausal women
Authors: Draper Michael W. , Flowers David E. , Huster William J. , Neild Julie A. , Harper Kristine D. , Arnaud Claude 
Published: February 2010

Abstract
This randomized, double-blind, placebo-controlled, multicenter, 8-week study evaluated short-term effects of raloxifene on bone turnover, serum lipids, and endometrium in healthy, postmenopausal women. A total of 251 women received either placebo, raloxifene HCl 200 or 600 mg/day, or conjugated estrogens (Premarin, 0.625 mg/day). Bone turnover (serum alkaline phosphatase, serum osteocalcin, urinary pyridinoline cross-links, urinary calcium excretion, urinary hydroxyproline) and serum lipids (total serum cholesterol, high- and low-density lipoprotein cholesterol [HDL-C and LDL-C]) were evaluated at weeks 0, 2, 4, and 8. Endometrial biopsies were performed at weeks 0 and 8. Treatment groups were compared for each parameter for baseline-to-endpoint changes. The estrogen and raloxifene groups experienced similar decreases in serum alkaline phosphatase (range 10–11%), serum osteocalcin (range 21–26%), urinary pyridinoline cross-links (range 20–26%), and urinary calcium excretion (range 45–72%). These decreases differed significantly compared with placebo-treated subjects for all markers except serum osteocalcin, the raloxifene HCl 200 mg group. LDL-C decreased significantly in the estrogen and both raloxifene groups (range 5–9%) compared with placebo-treated subjects. HDL-C increased significantly in the estrogen group (16%) but was unchanged in the raloxifene groups. HDL-C:LDL-C ratios increased significantly in the estrogen and raloxifene groups (range 9–29%). Serum cholesterol decreased significantly in both raloxifene groups (range 4–8%) but was unchanged in the estrogen group. Uterine biopsies of raloxifene-treated subjects showed no change in the endometrium during this short-term treatment. Biopsies of the estrogen group showed significant endometrial stimulation. The only adverse event possibly related to raloxifene was vasodilatation (hot flashes) which was most common in the raloxifene HCl 600 mg group. Study results indicate that raloxifene may provide beneficial effects to bone and serum lipids in humans without uterine stimulatory effects.