bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin-6 and the acute phase response during treatment of patients with paget's disease with the nitrogen-containing bisphosphonate dimethylaminohydroxypropylidene bisphosphonate
Authors: Schweitzer Dave H. , Oostendorp-van de Ruit Marjanne , van der Pluijm Gabri , Löwik Clemens W.G.M. , Dr. Papapoulos Socrates E. 
Published: February 2010

Abstract
Bisphosphonates suppress bone resorption and are used in the management of bone diseases with increasing frequency. In some patients treated for the first time with potent nitrogen-containing bisphosphonates, there is a transient febrile reaction and transient hematological changes suggestive of an acute phase response. Because IL-6 is considered to be an important mediator of the acute phase response, we examined the changes in circulating IL-6 bioactivity in 38 patients with Paget's disease treated with the nitrogen-containing bisphosphonate (3-dimethyl- amino-1-hydroxypropylidene)-1,1-bisphosphonate (dimethyl-APD). 16 patients who had never received such bisphosphonate were treated with oral dimethyl-APD (100–400 mg/day) and 22 (9 for the first time) with intravenous dimethyl-APD 4 mg/day. Treatment was given for 10 days. Eleven of 38 patients, all first treatments, showed an increase in body temperature of more than 0.5°C exceeding 37°C associated with a significant decrease in lymphocyte count and an increase in serum CRP values. These changes were transient and did not occur in the patients with no febrile response. In patients with a febrile reaction circulating IL-6 bioactivity increased significantly and this increase generally preceeded the rise in temperature. Moreover, patients with an acute phase response had significantly higher peak IL-6 values than those without (128 ± 30 vs. 31 ± 4 U/ml, p &lt; 0.001). The peaks in plasma IL-6 were further correlated with the peaks in temperature and in serum CRP values (r = 0.49, p &lt; 0.05). In vitro, low concentrations of dimethyl-APD, but not of clodronate, stimulated IL-6 release from fetal mouse bone explants and this release was markedly enhanced after treatment of the bones with dimethyl-APD followed by PTH. There was also a significant correlation between basal plasma PTH concentrations and IL-6 peaks (r = 0.60, p &lt; 0.005) in the patients that improved further when only results from patients with first time exposure to dimethyl-APD were analyzed (r = 0.88, p &lt; 0.002). In conclusion, an acute phase response occurred only in patients treated for the first time with the nitrogen-containing bisphosphonate dimethyl-APD and IL-6 plays a role in this response. The cellular basis of the interaction between bisphosphonates and IL-6 at the bone-bone marrow interface remains to be elucidated.
Short-term local injections of transforming growth factor-β1 decrease ovariectomy-stimulated osteoclastic resorption in vivo in rats
Authors: Beaudreuil Johann , Mbalaviele Gabriel , Cohen-Solal Martine , Morieux Caroline , de Vernejoul Marie Christine , Orcel Philippe 
Published: February 2010

Abstract
Estrogen deficiency in rats is responsible for increased osteoclastic resorption and a subsequent rapid bone loss. TGF-β, which is known to have acute effects on bone resorption in several in vitro models, has been shown to be secreted by osteoblastic cells in vitro in response to 17β-estradiol, but little is known about its in vivo effects on bone resorption. We therefore decided to investigate the short-term effect of TGF-β1 on bone resorption in ovariectomized rats. TGF-β1 (0.04–20 ng/injection), or vehicle, was injected daily directly into the bone marrow space, through a thin catheter implanted in the distal end of the right femur, during 4 consecutive days, starting 14 days after the ovariectomy. Bone histomorphometry was performed in the secondary spongiosa of the metaphysis of injected femurs and compared with vehicle-injected femurs of sham ovariectomized rats. Ovariectomy was associated with a marked increase in the resorption surface, a 2-fold increase in the number of osteoclasts, and no change in the number of TRAP-positive marrow cells distant from bone surfaces. Bone resorption was significantly lower in the TGF-β1-injected bones of ovariectomized rats, as compared with vehicle injected bones: the osteoclast surface and the number of osteoclasts were, respectively, 11.0 ± 5.1% versus 20.8 ± 1.3% and 287 ± 41 versus 505 ± 53, in bones injected with 0.2 ng of TGF-β1 as compared with vehicle-injected bones (mean ± SE, p &lt; 0.05). The bone formation rate, assessed by double tetracycline labeling, was increased in ovariectomized rats, but was significantly decreased in TGF-β1-injected bones (2 and 20 ng/injection) of ovariectomized rats. The trabecular bone volume was decreased in ovariectomized animals, but was not modified in TGF-β1-injected bones in this short-term experiment. We conclude that, when injected into bones of ovariectomized rats, TGF-β1 attenuates the stimulation of osteoclastic resorption induced by estrogen deficiency. These data therefore suggest that a local failure of TGF-β secretion could be partly responsible for the stimulation of bone resorption and subsequent bone loss due to the cessation of the ovarian secretion.
Vitamin D receptor alleles and rates of bone loss: Influences of years since menopause and calcium intake
Authors: Krall Elizabeth A. , Parry Pauline , Lichter Jay B. , Dr. Dawson-Hughes Bess 
Published: February 2010

Abstract
A genetic marker for the 1,25-dihydroxyvitamin D receptor (VDR) is reported to account for much of the heritable component of bone density. It is not known whether VDR genotype influences bone accretion or loss, or how it is related to calcium metabolism. The VDR genotype was determined in 229 healthy postmenopausal women who previously participated in a calcium trial. VDR alleles were designated according to presence (b) or absence (B) of the BsmI restriction enzyme cutting site. There were 83 bb, 102 Bb, and 44 BB individuals. Two-thirds of the women took 500 mg of calcium supplement (mean calcium intake = 892 mg/day) and one-third a placebo (mean = 376 mg/day). Bone mineral density (BMD) at the femoral neck, spine, and radius were measured by dual- and single-photon absorptiometry at baseline and after 1 and 2 years. Among women more than 10 years postmenopausal, those with the BB genotype had the lowest femoral neck BMD. Rates of bone loss over 2 years were greater in the BB group at all sites (e.g., at the femoral neck, bb, 0.45 ± 0.43; Bb, -0.01 ± 0.40; BB, -0.99 ± 0.50%/year; BB vs. bb, p = 0.01), and this trend was found both in women &lt;10 years since menopause (e.g., at the radius, bb, 0.43 ± 0.47; Bb, -0.37 ± 0.42; BB, -1.20 ± 0.59% per year; BB vs. bb, p = 0.02) and those ≥10 years (radius, bb, -0.71 ± 0.41; Bb, 0.08 ± 0.39; BB, -1.41 ± 0.49% per year; BB vs. Bb, p &lt; 0.01). At the femoral neck, bone loss appeared to be modified by calcium intake (e.g., in the BB genotype: +0.03 ± 0.61 in supplemented vs. -2.01 ± 0.75%/year in placebo, in bb: 0.57 ± 0.58 vs. 0.32 ± 0.47%/year; interaction term p = 0.09), and this trend was also present in both early and late menopause. Rates of change at the radius and spine in BB were not significantly influenced by calcium at the intake levels of this study group. These results indicate that postmenopausal bone loss is influenced by the VDR genotype and suggest the adverse effect of the susceptible allele at the hip may be reduced by raising calcium intake.
The contribution of vitamin D receptor gene alleles to the determination of bone mineral density in normal and osteoporotic women
Authors: Dr. Riggs Lawrence B. , Nguyen Tijan V. , Melton Joseph L. , Morrison Nigel A. , O'Fallon William M. , Kelly Paul J. , Egan Kathleen S. , Sambrook Philip N. , Muhs Joan M. , Eisman John A. 
Published: February 2010

Abstract
Bone mass and its mineral content are under genetic control. The vitamin D receptor (VDR) gene has been shown to be a major locus for genetic effects on bone mineral density (BMD), and polymorphisms in this gene accounted for a large proportion of genetic variance in BMD in an Australian population. In this study, we investigated whether similar associations are present in a North American population. We studied 139 normal healthy women (age 53.2 ± 14.5, mean ± SD) and 43 severely osteoporotic postmenopausal women (age 65.8 ± 5.9). In the 127 of them with complete genetic studies, the distribution of genotypes, determined by polymerase chain reaction on leukocyte DNA samples, agreed closely with that in the Australian population. BMD was strongly related to age and weight, and, thus was adjusted for these parameters prior to genetic analysis. We found that age modulated the effect of VDR genotypes on femoral neck BMD (FN-BMD) (TaqI, p = 0.036;BsmI, p = 0.118; ApaI, p = 0.041) such that the effect of genotype was greatest among younger (premenopausal) women and declined with age so that there was no discernible difference by age 70. Among the younger women, a high FN-BMD was associated with the TT (or aa or bb) genotype while low FN-BMD was associated with the tt (or AA or BB) genotype. In osteoporotic women, although the difference in FN-BMD between alternate TaqI homozygotes (TT vs. tt) was 0.13 g/cm2 (or about 18%), the overall difference among the genotype groups was not significant (TaqI, p = 0.13; BsmI, p = 0.21; ApaI, p = 0.09), possibly due to the small sample of osteoporotic women. There was no relationship of VDR genotype to lumbar spine BMD. We conclude that the VDR gene modulates differences in BMD in premenopausal women. Subsequent interaction of the gene and environmental factors and the role of VDR genotypes in predisposing to osteoporosis needs further study.
Effects of fluoridated drinking water on bone mass and fractures: The study of osteoporotic fractures
Authors: Cauley Jane A. , Buhari Alhaji M. , Murphy Patricia A. , Riley Theodore J. 
Published: February 2010

Abstract
To determine if optimal fluoridation of public water supplies influences bone mass and fractures, we studied 2076 non-black women, all aged ≥65 years recruited into the Study of Osteoporotic Fractures at the Pittsburgh clinic. Information on fluoride exposure was limited to community water supplies. The variable used in the analysis was years of exposure to fluoridated water in community drinking water supplies. Bone mineral density (BMD) was measured at the spine and hip using dual energy X-ray absorptiometry and at the midpoint and ultradistal radius and calcaneus using single photon absorptiometry. Prevalent and incident vertebral fractures were determined by morphometry. Incident nonspine fractures were ascertained every 4 months and confirmed by radiographic report. Exposure to residential fluoridated water had no effect on bone mass. Women exposed to fluoride for &gt;20 years had similar axial and appendicular bone mass to women not exposed or women exposed for ≤20 years. There was some suggestion that women exposed to fluoride for &gt;20 years had a lower relative risk of nonspine fractures (relative risk, RR, = 0.73; 95% confidence interval [CI] 0.48–1.12), osteoporotic fractures, RR = 0.74 (CI 0.46–1.19), and hip fractures, RR = 0.44 (CI 0.10–1.86), compared with women not exposed, but none of these relative risks was statistically significant. There was no association with wrist or spinal fractures. Our results do not support the findings from recent ecological studies which showed an increased risk of hip fracture among individuals exposed to fluoridated public water. (
The effects of intravenous alendronate in Paget's disease of bone
Authors: O'Doherty D.P. , Mccloskey E.V. , Vasikaran S. , Khan S. , Kanis J.A. 
Published: February 2010

Abstract
We studied the effects of intravenous alendronate on disease activity in 36 patients with active Paget's disease of bone. Alendronate was administered to 3 groups of 12 patients at doses of 2.5, 5, and 10 mg intravenously daily for 5 consecutive days. The patients were matched for disease activity. Symptomatic improvement was seen in at least 10 patients in each treatment group. Alendronate induced a dose-dependent suppression of biochemical indices of bone turnover in all patients. A significant reduction in the mean fasting urinary excretion of hydroxyproline occurred within 2 days of starting treatment, reaching a nadir at 2–4 weeks, which was most marked in patients receiving 10 mg of alendronate (p &lt; 0.05). There was a slower fall in serum alkaline phosphatase activity with maximal suppression occurring 3 months after the start of treatment. The degree of suppression was least for those receiving 2.5 mg of alendronate (p &lt; 0.05) but no difference in response was observed for the other dosages. The duration of response was also dose-related. A significant fall in the serum calcium and urinary excretion of calcium occurred from the second day of treatment but returned to pretreatment values by 4 months. A transient fall in the mean lymphocyte count was observed, which was similar for each group. This was associated with a short-lived fever in 3 patients receiving 10 mg, in 4 patients receiving 5 mg, and in 2 patients receiving 2.5 mg. We conclude that intravenous alendronate, 5–10 mg/day for 5 days, induces a more complete suppression of bone resorption than the lower dose and provides durable long-term control of Paget's disease. (
Estimates of volumetric bone density from projectional measurements improve the discriminatory capability of dual X-ray absorptiometry
Authors: Jergas Michael , Breitenseher Martin , Glüer CLAUS-C. , Yu Wei , Genant Harry K. 
Published: February 2010

Abstract
To determine whether estimates of volumetric bone density from projectional scans of the lumbar spine have weaker associations with height and weight and stronger associations with prevalent vertebral fractures than standard projectional bone mineral density (BMD) and bone mineral content (BMC), we obtained posteroanterior (PA) dual X-ray absorptiometry (DXA), lateral supine DXA (Hologic QDR 2000), and quantitative computed tomography (QCT, GE 9800 scanner) in 260 postmenopausal women enrolled in two trials of treatment for osteoporosis. In 223 women, all vertebral levels, i.e., L2–L4 in the DXA scan and L1–L3 in the QCT scan, could be evaluated. Fifty-five women were diagnosed as having at least one mild fracture (age 67.9 ± 6.5 years) and 168 women did not have any fractures (age 62.3 ± 6.9 years). We derived three estimates of “volumetric bone density” from PA DXA (BMAD, BMAD*, and BMD*) and three from paired PA and lateral DXA (WA BMD, WA BMDHol, and eVBMD). While PA BMC and PA BMD were significantly correlated with height (r = 0.49 and r = 0.28) or weight (r = 0.38 and r = 037), QCT and the volumetric bone density estimates from paired PA and lateral scans were not (r = −0.083 to r = 0.050). BMAD, BMAD*, and BMD* correlated with weight but not height. The associations with vertebral fracture were stronger for QCT (odds ratio [OR] = 3.17; 95% confidence interval [CI] = 1.90–5.27), eVBMD (OR = 2.87; CI 1.80–4.57), WA BMDHol (OR = 2.86; CI 1.80–4.55) and WA-BMD (OR = 2.77; CI 1.75–4.39) than for BMAD*/BMD* (OR = 2.03; CI 132–3.12), BMAD (OR = 1.68; CI 1.14–2.48), lateral BMD (OR = 1.88; CI 1.28–2.77), standard PA BMD (OR = 1.47; CI 1.02–2.13) or PA BMC (OR = 1.22; CI 0.86–1.74). The areas under the receiver operating characteristic (ROC) curves for QCT and all estimates of volumetric BMD were significantly higher compared with standard PA BMD and PA BMC. We conclude that, like QCT, estimates of volumetric bone density from paired PA and lateral scans are unaffected by height and weight and are more strongly associated with vertebral fracture than standard PA BMD or BMC, or estimates of volumetric density that are solely based on PA DXA scans.
The effects of analytic software and scan analysis technique on the comparison of dual X-ray absorptiometry with dual photon absorptiometry of the hip in the elderly
Authors: Kiel Douglas P. , Cali Clorinda , Mercier Cherlyn A. , Dawson-Hughes Bess , Hannan Marian T. , Anderson Jennifer J. 
Published: February 2010

Abstract
As part of a longitudinal comparison of bone mineral density (BMD) results originally obtained using a Lunar dual photon absorptiometry (DPA) scanner and later, using a Lunar dual X-ray absorptiometry (DXA) scanner, we compared femur results between DPA and DXA according to DXA analytic software (versions 1.3y and 1.4), and according to the method of placement of the femoral neck box (software algorithm or operator placement according to the appearance of the pair of images) in 58 elderly men and women. The mean BMD at each of three femoral sites was higher using DXA version 1.3y than DPA, but the use of software version 1.4 brought the BMD value closer to that of DPA at all sites. Of 58 scans, 12 (21%) were changed by the operator, resulting in an overall reduction in mean percent BMD difference between scan pairs of 79% (from 1.24% to 0.29%). Although the differences between the DPA/DXA software-driven analysis and the DPA/DXA operator-driven analysis appeared small (high r2 values and intra-class correlation coefficients), the increase in sample size that would be required for the same power to detect 2-year changes in BMD if the software-driven analysis was used instead of taking the time to perform the operator-driven analysis was 18%. The findings of this study highlight the need to account for upgrades in analytic software. Furthermore, we present a rational approach for the analysis of serial scans that has face validity and that results in smaller differences between pairs of scans performed on the same individual. The decision to adapt these methods must be based on the relative costs of reducing unwanted scan variability.
Effect of prostaglandin E2 on phospholipase D activity in osteoblast-like MC3T3-E1 cells
Authors: Oiso Yutaka , Suzuki Atsushi , Kozawa Osamu 
Published: February 2010

Abstract
Recent evidence indicates that phosphatidylcholine breakdown by phospholipase D (PLD) is an important cellular control mechanism. We investigated the signaling pathway participating in prostaglandin E2 (PGE2)–induced PLD activation in osteoblast-like MC3T3-E1 cells. PGE2 stimulated PLD activity, as measured by choline generated from phosphatidylcholine, just after the stimulation. The reaction reached a plateau 15 minutes later. PGE2 stimulated PLD activity in a dose-related manner and also increased inositol phosphate (IP) formation. However, the EC50 value for PGE2-induced IP formation is lower than that for PLD activation. 12-O-Tetradecanoylphorbol-13-acetate (TPA), a protein kinase C (PKC) activator, stimulated PLD activity, and a combination of PGE2 and TPA potentiated it in an additive manner. Although NaF, a heterotrimeric GTP-binding protein activator, significantly stimulated PLD activity, this effect was not augmented by combination with PGE2. PGE2-induced PLD activity was markedly suppressed by either chelating extracellular Ca2+ by EGTA or pertussis toxin. These findings suggest that osteoblasts might have at least two PLD activation mechanisms which involve PKC-dependent or -independent pathways. However, present results indicate that PKC is unlikely to be essential to PGE2-induced PLD activation. On the contrary, pertussis toxin-sensitive GTP-binding protein and extracellular Ca2+ might play important roles in the pathway of PGE2-induced PLD activation.
Intravenous pamidronate in patients with tumor-induced osteolysis: A biochemical dose-response study
Authors: Body J. J. , Dumon J. C. , Piccart M. , Ford J. 
Published: February 2010

Abstract
Bisphosphonates are used increasingly in normocalcemic patients for treating tumor-induced osteolysis (TIO) but little is known about the metabolic effects and the most appropriate therapeutic regimen. In 21 patients with breast cancer and TIO, we determined the biochemical effects of a single infusion of pamidronate given at 30 mg (n = 5), 60 mg (n = 5), 90 mg (n = 5), or 120 mg (n = 6). Patients received no other systemic antineoplastic therapy during the trial. We selected patients with baseline fasting urinary Ca/Creat (creatinine) &gt;0.105 mg/mg (median value of our normal range) and they were followed weekly for up to 14 weeks. The biochemical effects were maximal at day 7. For the whole group, mean (± SEM) Ca/Creat levels fell from 0.208 ± 0.018 to 0.048 ± 0.008 mg/mg on day 7 and remained significantly (p &lt; 0.01) lower than baseline up to day 56. Hydroxyproline excretion fell to a lesser degree, from 7.0 ± 1.2 to 4.0 ± 0.6 mg × 100/mg of Creat. The falls in Ca/Creat and hydroxyproline excretion were dose-related (ANCOVA, p &lt; 0.05). Changes in serum parameters of calcium metabolism were, however, not significantly dose-related. Serum Ca levels fell from 9.3 ± 0.1 to 8.7 ± 0.1 mg/dl on day 7, but no patients developed symptomatic hypocalcemia, and the decrease within each dose group was significant only at 120 mg. Ca2+ levels followed a similar pattern. There was a slight increase in Mg levels and a pronounced fall in Pi levels, from 3.6 ± 0.2 to 2.8 ± 0.1 mg/dl. Intact PTH levels increased from 29 ± 4 to 91 ± 13 pg/ml and remained significantly (p &lt; 0.05) elevated up to day 28. The concentration of 1,25(OH)2 vitamin D increased from 20 ± 2 to 45 ± 4 pg/ml, but the osteocalcin concentration did not change significantly. We subsequently treated 11 cancer patients with bone metastases and low urinary Ca/Creat levels (&lt;0.105 mg/mg) with 30 or 60 mg of pamidronate. The changes in biochemical parameters of bone metabolism were similar to those described above, confirming the safety of these doses of pamidronate in patients without evidence of increased bone resorption. In summary, single pamidronate infusions, given at doses from 30 to 120 mg, dose-dependently inhibited bone resorption in patients with bone metastases. Pamidronate also induced marked but transient changes in blood parameters of calcium metabolism, especially at a dose of 120 mg. Our data suggest that 90 mg of pamidronate is adequate to inhibit bone resorption in this patient population.