bluuebunny/crossref_metadata_2025_split huggingface dataset:
Profound Hypogonadism Has Significant Negative Effects on Calcium Balance in Males: A Calcium Kinetic Study
Authors: Mauras Nelly , Hayes Valerie Y. , Vieira Nancy E. , Yergey Alfred L. , O'brien Kimberly O. 
Published: April 2006

Abstract
The impact of estrogen deficiency on bone has been extensively studied in the female; however, the effects of androgen deficiency on calcium fluxes in males have been less well characterized. We investigated the effect of short-term, severe androgen deficiency on measures of calcium absorption and kinetics as well as on markers of bone turnover in males. To accomplish this, 11 healthy male volunteers were recruited (mean age 23.3 ± 0.5 years [SEM], body mass index 25.3 ± 0.8 kg/m2). They consumed a weight maintenance diet for at least 3 days prior to admission to our Research Unit, with a calcium intake of ∼1200 mg/day. At baseline (D1), subjects received42Ca intravenously as well as44Ca PO mixed with milk or juice. A 29-h urine collection was begun and blood samples collected at frequent intervals for the measurement of the isotopic enrichment of42Ca and44Ca using thermal ionization mass spectrometry. Twice daily urine samples were collected for 5 days after the administration of the isotopes. A gonadotropin-releasing hormone agonist (Lupron) was given after D1, again 3 weeks later, and studies repeated identically 4 weeks (D2, n = 6) and 10 weeks from baseline (D3, n = 7) (two subjects completed three studies). Testosterone concentrations were markedly suppressed on both D2 and D3 (−95%, p &lt; 0.006), whereas there were no detectable changes in growth hormone and insulin-like growth factor-1 concentrations. Urinary calcium excretion increased significantly after 4 weeks (43%, p = 0.0007) and 10 weeks (73%, p = 0.003) of sustained hypogonadism. Using a multicompartmental kinetic model, the contribution of oral calcium to the urinary losses was decreased by D3 (−41%, p = 0.01), yet the contribution of bone calcium to urine losses increased by 10 weeks (+11%, p = 0.01). There was a 21% decrease in bone calcium deposition (Vo+) by D3 (p &lt; 0.05) with no significant change in bone resorption rates (Vo−). There was a significant correlation between the decrease in testosterone concentration and the increase in urinary calcium excretion, especially at 10 weeks (R2 = 0.84, p = 0.004). These kinetic changes were accompanied by a decrease in osteocalcin concentrations on D2, with improvements by D3. Urinary N telopeptide, a measure of bone resorption, also increased during the studies. In summary, profound hypogonadism in young males is associated with marked increases in urinary calcium losses, with a greater contribution of bone calcium to those losses and decreased kinetic markers of bone calcium deposition. We conclude that even short-term, severe deficiency in gonadal steroids can have profound negative effects on calcium and bone metabolism in males.
Monitoring Alendronate Therapy for Osteoporosis
Authors: De castro machado Adriana Braga , Hannon Rosemary , Prof. Eastell Richard 
Published: April 2006

Abstract
Alendronate is an antiresorptive therapy for osteoporosis and results in a decrease in bone turnover. To choose the optimal measurement for monitoring this therapy, the size of the change needs to be compared with the variability of the measurement. We studied 26 women with postmenopausal osteoporosis (bone mineral density [BMD] T score &lt; –2.5), who were randomized in a 2:1 ratio to receive alendronate (10 mg/day) and calcium carbonate (500 mg/day) or calcium carbonate alone for 6 months. We measured serum markers of bone formation (osteocalcin [OC], bone isoform of alkaline phosphatase [BAP], and collagen type I C-terminal propeptide [CICP]) and urinary markers of bone resorption (cross-linked N-telopeptide [NTx], free deoxypyridinoline [iFDpd], and free pyridinolines). All subjects had two measurements 1 week apart at baseline to calculate the short-term variability. Biochemical measurements were then made at 4, 8, 12, 24, and 25 weeks. Measurements of bone mass were made by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and proximal femur twice at baseline and then at 24 and 25 weeks. The mean difference in change in BMD and markers between both groups at the end of the study that were significant were (short-term variability in brackets): DXA total hip 4.3% (2.5%), NTX 49% (10%), iFDpd 22% (12%), OC 28% (13%), BAP 31% (13%), and CICP 31% (11%). Five of the six markers showed significant responses to alendronate therapy, but they differed in the relationship between size of response and variability. These biochemical markers performed better than DXA for monitoring alendronate therapy over 6 months.
Alteration in the Mechanical Competence and Structural Properties in the Femoral Neck and Vertebrae of Ovariectomized Rats
Authors: Peng Zhiqi , Tuukkanen Juha , Zhang Hongxue , Väänänen H. Kalervo 
Published: April 2006

Abstract
The structural and mechanical properties of bone in the femoral neck and various other sites were investigated in intact (INT), sham-operated (Sham), and ovariectomized (OVX) rats. Six weeks after operation, the maximal load and energy absorption of the femoral neck were significantly lower in the OVX than in the INT or Sham groups, being 73.2 ± 1.4 (SE) N, 86.3 ± 4.1 N, and 87.1 ± 3.2 N, respectively (p &lt; 0.01) for load. The total cross-sectional area of the femoral neck did not change after OVX, but the marrow cavity area was enlarged, leading to a reduced bone area (including both cortical and trabecular bone) (p &lt; 0.01). Histomorphometric analysis showed that new bone formation could not be detected at the periosteum of the femoral neck below the femoral head, but at the endocortical surfaces the double tetracycline labeling revealed an increased mineral apposition rate (MAR) and bone formation rate (BFR) in OVX animals (p &lt; 0.001). In contrast, MAR and BFR were significantly increased in both periosteal and endocortical surfaces of the tibia, humerus, and femoral shaft, thus preventing a decrease in cortical bone area. The maximal bending loads of the tibia and humerus were not different in the various groups of animals. The correlation coefficient between maximal load and bone area revealed positive relationships in the femoral neck (r = 0.54, p &lt; 0.01), tibia (r = 0.46, p &lt; 0.01), and humerus (r = 0.51, p &lt; 0.01). Ovariectomy resulted in a decreased trabecular bone volume of lumbar vertebra VI (L6) decreased compressive loads of lumbar vertebrae I, III, and IV. These lumbar bone loads were positively related to their L6 bone area (L4/L6: r = 0.66, p &lt; 0.001). Element analyses (energy dispersion spectrometer) from trabecular and cortical areas of bone showed some changes related to aging but not to OVX. These results indicate that ovariectomy influences the biomechanical properties of rat bone by changing structural properties rather than material ones.
Determinants of Peak Bone Mass: Clinical and Genetic Analyses in a Young Female Canadian Cohort
Authors: Dr. Rubin Laurence A. , Hawker Gillian A. , Peltekova Vanya D. , Fielding Lynda J. , Ridout Rowena , Cole David E. C. 
Published: April 2006

Abstract
Peak bone mass has been shown to be a significant predictor of risk for osteoporosis. Previous studies have demonstrated that skeletal mass accumulation is under strong genetic control, and efforts have been made to identify candidate loci. Determinants of peak bone mass also include diet, physical activity, hormonal status, and other clinical factors. The overall contribution of these factors, genetic and nongenetic, and their interaction in determining peak bone density status have not been delineated. Six hundred and seventy-seven healthy unrelated Caucasian women ages 18–35 years were assessed. A detailed, standardized interview was conducted to evaluate lifestyle factors, menstrual and reproductive history, medical conditions, medication use, and family history of osteoporosis. Bone mineral density (BMD) was measured at the lumbar spine (L2–L4) and the femoral neck (hip) using dual-energy X-ray absorptiometry. Genotyping of the vitamin D receptor (VDR) locus at three polymorphic sites (BsmI, ApaI, and TaqI) was performed. In bivariate analyses, BMD at the lumbar spine and hip was positively correlated with weight, height, body mass index (BMI), and level of physical activity, both now and during adolescence, but negatively correlated with a family history of osteoporosis. Hip, but not spine BMD, correlated positively with dietary intake of calcium, and negatively with amenorrhea of more than 3 months, with caffeine intake, and with age. Spine, but not hip BMD, correlated positively with age and with number of pregnancies. VDR haplotype demonstrated significant associations with BMD at the hip, level of physical activity currently, and BMI. In multivariate analysis, independent predictors of greater BMD (at the hip or spine) were: age (younger for the hip, older for the spine), greater body weight, greater height (hip only), higher level of physical activity now and during adolescence, no family history of osteoporosis, and VDR genotype (hip only). Weight, age, level of physical activity, and family history are independent predictors of peak BMD. Of these factors, weight accounts for over half the explained variability in BMD. VDR alleles are significant independent predictors of peak femoral neck, but not lumbar spine BMD, even after adjusting for family history of osteoporosis, weight, age, and exercise. However, the overall contribution of this genetic determinant is modest. Taken together, these factors explained ∼17% and 21% of the variability in peak spine and hip BMD, respectively, in our cohort. Future research should be aimed at further evaluation of genetic determinants of BMD. Most importantly, understanding the critical interactive nature between genes and the environment will facilitate development of targeted strategies directed at modifying lifestyle factors as well as earlier intervention in the most susceptible individuals.
Developmental Regulation of Nitric Oxide Synthase Expression in Rat Skeletal Bone
Authors: Hukkanen Mika V. J. , Platts Louise A. M. , De Marticorena Iñigo Fernandez , O'Shaughnessy Meg , Macintyre Iain , Polak Julia M. 
Published: April 2006

Abstract
Nitric oxide (NO) has been implicated in bone growth and remodeling by studies showing that inhibition of NO-synthase (NOS) activity retards normal gain in bone mineral density both during skeletal development and after sexual maturity. In the present study, we aimed to assess the level of expression and cellular localization of the three NOS isoforms during skeletal bone development from neonatal to sexual maturity in female Wistar rats. Reverse transcription polymerase chain reaction (RT-PCR) was used to analyze the presence of NOS1 (neuronal), NOS2 (inducible), and NOS3 (endothelial) transcripts in femoral bone from neonatal, 4-, 8-, and 12-week-old rats. RT-PCR amplified NOS1, NOS2, and NOS3 transcripts of 472-, 807-, and 289-bp, respectively. There were no detectable differences in the levels of NOS1 mRNA between the groups; however, NOS2 mRNA was more abundant in the neonatal group compared with 4-, 8-, and 12-week groups. Expression of NOS1 protein could not be detected in bones by either Western blotting or immunocytochemistry in any of the age groups investigated. Western blots for NOS2 revealed expression in the neonatal group only and it was not detected in any of the older age groups. Immunostaining for NOS2 was also most evident in the neonatal group and was localized specifically to trabecular osteoblasts and osteoclasts. In all age groups studied, NOS3 mRNA and protein were found in bone-resorbing osteoclasts, cuboidal active osteoblasts, and osteocytes. Semiquantitative RT-PCR provided evidence of down-regulation of NOS3 transcripts during the skeletal development. This was confirmed using in situ hybridization, which showed higher expression in neonatal and 4-week groups than in other groups. Western blots and counting the ratio of trabecular osteoblasts that were NOS3 immunoreactive showed parallel down-regulation of NOS3 protein during skeletal development. Taken together, these data show that there is regulation of NOS2 and in particular NOS3 expression during skeletal development and this may be significant to trabecular bone growth and remodeling.
The Role of the Plasminogen System in Bone Resorption In Vitro
Authors: Daci E. , Udagawa N. , Martin T. J. , Bouillon R. , Carmeliet G. 
Published: April 2006

Abstract
The plasminogen/plasmin proteolytic cascade plays an important role in extracellular matrix remodeling. The presence of the two plasminogen activators (PAs), tissue-type plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA), and their inhibitor type 1 (PAI-1) in bone cells, suggests a role in one or more aspects of bone resorption such as osteoclast formation, mineral dissolution, and degradation of the organic matrix. These different processes were assayed in vitro using cells derived from mice with either tPA (tPA−/−), uPA (uPA−/−), PAI-1 (PAI-1−/−) inactivation or with a combined inactivation (tPA−/−:uPA−/−) and compared with wild-type mice (WT). First, osteoclast formation, assessed by investigating the number and characteristics of tartrate-resistant acid phosphatase–positive multinucleated cells formed in cocultures of primary osteoblasts and bone marrow cells treated with 1α,25-dihydroxyvitamin D3, was not different between the different cell types. Second, dentine resorption, an assay for osteoclast activity, was not affected by the combined deficiency of both tPA and uPA. Finally, the ability to degrade nonmineralized bone-like matrix was however, significantly reduced in tPA−/−:uPA−/− cells compared with WT cells (28.1 ± 0.6%, n = 6 vs. 56.4 ± 3.1%, n = 6, respectively, p &lt; 0.0001). Surprisingly, collagen proteolysis by bone cells was not dependent on the presence of plasmin as suggested by degradation assays performed on type I3H-collagen films. Taken together, these data suggest that the plasminogen activator/plasmin system is not required for osteoclast formation, nor for the resorption of the mineral phase, but is involved in the removal of noncollagenous proteins present in the nonmineralized bone matrix.
Systemic Administration of Acidic Fibroblast Growth Factor (FGF-1) Prevents Bone Loss and Increases New Bone Formation in Ovariectomized Rats
Authors: Dunstan C. R. , Boyce R. , Boyce B. F. , Garrett I. R. , Izbicka E. , Burgess W. H. , Mundy G. R. 
Published: April 2006

Abstract
There are no universally accepted agents that will substantially increase bone mass in osteoporotic patients. A number of peptides important in normal bone formation, such as members of the transforming growth factor-β superfamily, are not satisfactory for this purpose either because their beneficial effects are predominantly local or there is systemic toxicity associated with their administration. We have examined the effects of exogenous fibroblast growth factor-1 and -2 (FGF-1 and FGF-2) on bone in vivo, since FGFs have been shown recently to be essential for normal skeletal development. FGF-1 was injected daily (0.2 mg/kg intravenously) for 28 days into the tail vein of adult female rats immediately following and 6 months after sham operation or ovariectomy (OVX). In rats treated immediately post-OVX, OVX produced more than a 30% decrease in tibial bone density, which was prevented by FGF-1 and estrogen. However, FGF-1 also had an anabolic effect. In sham-operated rats, FGF-1 increased bone density to 2-fold, whereas estrogen had no effect. In rats 6 months post-OVX, severe bone loss and disruption of trabecular microarchitecture occurred similar to that seen in patients with severe osteoporosis. In these rats, administration of FGF-1 induced extensive new woven bone formation with new trabecular-like structures filling much of the marrow spaces, and bone density in the tibial metaphysis increased 3-fold. FGF-1 and FGF-2 were also administered subcutaneously over the calvaria of mice in doses of 2–2000 μg/day for 3 days and shown to produce substantial increases in bone formation when examined morphologically. Thus, we conclude that both local and systemic FGF-1 increases new bone formation and bone density, and systemic FGF-1 also appears to restore bone microarchitecture and prevent bone loss associated with estrogen-withdrawal.
Midkine Is Expressed During Repair of Bone Fracture and Promotes Chondrogenesis
Authors: Ohta Susumu , Muramatsu Hisako , Senda Takao , Zou Kun , Iwata Hisashi , Muramatsu Takashi 
Published: April 2006

Abstract
Midkine (MK) is a heparin-binding growth/differentiation factor implicated in the control of development and repair of various tissues. Upon fracture of the murine tibia, MK was found to be transiently expressed during bone repair. MK was immunohistochemically detected in spindle-shaped mesenchymal cells at the fracture site on day 4 after fracture and in chondrocytes in the area of endochondral ossification on day 7. MK expression was decreased on day 14 and scarcely seen on day 28 when bone repair was completed. This mode of MK expression is reminiscent of MK expression during development. MK was expressed in hypertrophic chondrocytes of the prebone cartilage rudiments on embryonic day 14 in mouse embryos. MK was also strongly expressed in the epiphyseal growth plate. MK was localized intracellularly during both bone repair and development, and this localization was confirmed by immunoelectron microscopy for embryonic chondrocytes. When MK cDNA was transfected into ATDC5 chondrogenic cells and overexpressed, the majority of transfected cells with strong MK expression showed enhanced chondrogenesis as revealed by increased synthesis of sulfated glycosaminoglycans, aggrecan, and type II collagen. These results suggest that MK plays important roles in chondrogenesis and contributes to bone formation and repair.
Dietary Conjugated Linoleic Acids Alter Serum IGF-I and IGF Binding Protein Concentrations and Reduce Bone Formation in Rats Fed (n-6) or (n-3) Fatty Acids
Authors: Li Yong , Seifert Mark F. , Ney Denise M. , Grahn Mike , Grant Alan L. , Allen Kenneth G. D. , Watkins Bruce A. 
Published: April 2006

Abstract
A study was designed to examine the effects of dietary conjugated linoleic acid (CLA) on serum concentrations of insulin-like growth factor-I (IGF-I) and IGF binding proteins (IGFBP) and the relationship of these factors to bone metabolism. Weanling male rats were fed AIN-93G diet containing 70 g/kg of added fat for 42 days. Treatments included 0 g/kg or 10 g/kg of CLA and soybean oil (SBO) or menhaden oil + safflower oil (MSO) following a 2 × 2 factorial design. Serum IGFBP was influenced by dietary polyunsaturated fatty acid (PUFA) type ((n-6) and (n-3)) and CLA (p = 0.01 for 38–43 kDa bands corresponding to IGFBP-3). CLA increased IGFBP level in rats fed SBO (p = 0.05) but reduced it in those fed MSO (p = 0.01). Rats fed MSO had the highest serum IGFBP-3 level. Both (n-3) fatty acids and CLA lowered ex vivo prostaglandin E2 production in bone organ culture. In tibia, rats given CLA had reduced mineral apposition rate (3.69 vs. 2.79 μm/day) and bone formation rate (BFR) (0.96 vs. 0.65 μm3/μm2/day); however, the BFR tended to be higher with MSO. Dietary lipid treatments did not affect serum intact osteocalcin or bone mineral content. These results showed that dietary PUFA type and CLA modulate local factors that regulate bone metabolism.
Oral Administration of the Growth Hormone Secretagogue MK-677 Increases Markers of Bone Turnover in Healthy and Functionally Impaired Elderly Adults
Authors: Murphy M. G. , Bach M. A. , Plotkin D. , Bolognese J. , Ng J. , Krupa D. , Cerchio K. , Gertz B. J. 
Published: April 2006

Abstract
Growth hormone (GH) stimulates osteoblasts in vitro and increases bone turnover and stimulates osteoblast activity when given to elderly subjects. Probably a major effect of GH on bone is mediated through stimulation of either circulating or locally produced insulin-like growth factor I (IGF-I). We determined the effect of chronic administration of the GH secretagogue, MK-677, on serum IGF-I and markers of bone turnover in 187 elderly adults (65 years or older) enrolled in three randomized, double-blind, placebo-controlled clinical studies lasting 2–9 weeks. Urine was collected for determination of N-telopeptide cross-links (NTXs), a marker of bone resorption, and blood was collected for determination of serum osteocalcin and bone-specific alkaline phosphatase (BSAP), as bone formation markers, and serum IGF-I levels pre- and post-treatment. Dose response data were initially obtained in healthy elderly subjects who received oral doses of 10 mg or 25 mg of MK-677 or placebo for 2 weeks (n = 10–12/group). Treatment with 10 mg and 25 mg of MK-677 for 2 weeks increased mean urine NTXs 10% and 17%, respectively (p &lt; 0.05 vs. placebo). Additionally, 50 healthy elderly subjects received either placebo (n = 20) for 4 weeks or 25 mg of MK-677 (n = 30) daily for 2 weeks followed by 50 mg daily for 2 weeks. MK-677 increased mean serum osteocalcin by 8% (p &lt; 0.05 vs. placebo). In both studies, MK-677 increased serum IGF-I levels significantly (55–94%). Subsequently, the biological effects of MK-677 were studied in 105 elderly subjects who met objective criteria for functional impairment. Subjects were randomized to receive oral doses of placebo for 9 weeks or either 5, 10, or 25 mg of MK-677 daily for an initial 2 weeks followed by 25 mg of MK-677 daily for the next 7 weeks(n = 63 on MK-677 and n = 28 on placebo completed 9 weeks of therapy). Treatment with MK-677 (all MK-677 groups combined) for 9 weeks increased mean serum osteocalcin by 29.4% and BSAP by 10.4% (p &lt; 0.001 vs. placebo) and mean urinary NTX excretion by 22.6% (p &lt; 0.05 vs. placebo). The change from baseline serum osteocalcin correlated with the change from baseline serum IGF-I in the MK-677 group (r = 0.37; p &lt; 0.01). In conclusion, once daily dosing with MK-677, an orally active GH secretagogue, stimulates bone turnover in elderly subjects based on elevations in biochemical markers of bone resorption and formation.