bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum Levels of Insulin-like Growth Factor Binding Proteins (IGFBP)–4 and –5 Correlate with Bone Mineral Density in Growth Hormone (GH)–Deficient Adults and Increase with GH Replacement Therapy
Authors: Thorén Marja , Hilding Agneta , Brismar Torkel , Magnusson Per , Degerblad Marie , Larsson Lasse , Sääf Maria , Baylink David J. , Mohan Subburaman 
Published: April 2006

Abstract
Adults with growth hormone deficiency (GHD) exhibit low bone mineral density (BMD) which improves by growth hormone (GH) replacement therapy. The insulin-like growth factor (IGF) system has an established role in mediating the effects of GH on bone and IGF binding proteins (IGFBP)-4 and IGFBP-5 have been shown to modulate the effects of IGFs in bone. Therefore, we studied serum levels of IGFBP-4 and IGFBP-5 and their relationship to serum levels of bone biochemical markers and BMD in adults with GH deficiency (GHD) before and during GH therapy. Serum levels of IGFBP-5 and IGFBP-4 were measured on samples from 20 patients (11 males) 22–57 years of age. All had IGF-I serum values below –2 standard deviation score. The first 6 months were placebo controlled and all recieved 3 years of active treatment with the mean dose 0.23 ± 0.01 IU/kg/week divided into daily subcutaneous injections. Serum IGFBP-5 levels in GHD adults were low at baseline and positively related to total body, femoral neck, trochanter, and Ward's triangle BMD (r = 0.471, 0.549, 0.462, and 0.470, respectively, p &lt; 0.05). The mean serum IGFBP-5 level increased by about 2-fold within 3 months after the initiation of GH therapy and was correlated with serum IGF-I (r = 0.719, 0.801, and 0.722 before and after 18 and 36 months, respectively, p &lt; 0.001). A positive correlation between serum IGFBP-5 levels and lumbar spine BMD was found during GH treatment but not before. The percentage increase of serum IGFBP-5 after GH therapy showed a positive correlation with the percentage increase of total alkaline phosphate activity (r = 0.347 p &lt; 0.05). In contrast to IGFBP-5, serum IGFBP-4 levels were positively related to body mass index (r = 0.607, p &lt; 0.01). Baseline serum IGFBP-4 levels also correlated with total body, femoral neck, trochanter, and Ward's triangle BMD (r = 0.502, 0.590, 0.612, and 0.471, respectively, p &lt; 0.05). The mean serum IGFBP-4 level was increased by 25% within 3 months after initiation of GH therapy and did not correlate with serum IGF-I levels. Although the above findings are consistent with the idea that GH-induced changes in serum IGFBP-5 and IGFBP-4 levels may in part mediate the anabolic effects of GH on bone tissue in adults with GHD, further studies are needed to establish the cause and effect relationship.
Paget's Disease of Bone
Authors: Siris Ethel S. 
Published: April 2006

Abstract
Paget's disease of bone is a localized disorder of bone remodeling. Increased numbers of larger than normal osteoclasts initiate the process at affected skeletal sites, and the increase in bone resorption is followed by an increase in new bone formation, altering bone architecture. The signs and symptoms of Paget's disease are varied, depending in part on the location of the involved sites and the degree of increased bone turnover. Recent progress in Paget's disease research includes new data regarding the etiology of this disorder and the ongoing development of more effective therapies. Although the cause of Paget's disease remains unproven, the creation of pagetic osteoclasts seems ever more likely to result from both genetic and environmental factors. Many studies indicate that in patients with Paget's disease, both osteoclasts and their precursors harbor evidence of a paramyxovirus infection, although not all studies confirm this finding. Very recent genetic investigations have identified one candidate gene on chromosome 18q, although genetic heterogeneity is almost certainly present. Advances in treatment have resulted from the availability of several potent bisphosphonate compounds (e.g., pamidronate, alendronate, and risedronate) that, unlike earlier treatments, produce normal or near normal bone turnover indices in a majority of patients. New bone formation after such treatment has a more normal, lamellar pattern, and mineralization abnormalities are rare to absent with the newer compounds. The availability of such agents has prompted a more aggressive management philosophy in which both symptomatic disease and also asymptomatic disease at sites with a risk of progression and future complications are viewed as clear indications for pharmacologic intervention.
Regulation of Prostaglandin G/H Synthase-2 Expression by Interleukin-1 in Human Osteoblast-like Cells
Authors: Min Yong-Ki , Rao Yue , Okada Yosuke , Raisz Lawrence G. , Pilbeam Carol C. 
Published: April 2006

Abstract
Interleukin-1 (IL-1) is an important factor in bone metabolism, and its actions may be mediated in part via prostaglandins. Prostaglandin G/H synthase (PGHS), a critical enzyme in the synthesis of prostaglandins, has two isoforms, PGHS-1, which is generally constitutively expressed, and PGHS-2, which is inducible. This study examines the effects of IL-1 on PGHS-2 mRNA expression in human osteosarcoma MG-63 cells, the human osteoblast-like initial transfectant (HOBIT) cell line, and primary human osteoblastic (HOB) cells. IL-1 induced PGHS-2 mRNA expression in MG-63 cells within 1 h, and expression was maintained for 24 h. There was a dose-related increase in PGHS-2 mRNA levels with 1–100 ng/ml of IL-1. Induction of PGHS-2 protein and media prostaglandin E2 (PGE2) paralleled induction of PGHS-2 mRNA levels. IL-1 similarly induced PGHS-2 mRNA expression and PGE2 production in HOBIT and HOB cells. Among other potential agonists, phorbol myristate acetate (PMA) was a potent inducer of PGHS-2 expression, while forskolin (FSK), serum, and prostaglandins had little effect. Cycloheximide enhanced effects of both IL-1 and PMA, suggesting that de novo protein synthesis is not required for induction of PGHS-2. Twenty-four hours of PMA pretreatment blocked the induction of PGHS-2 by PMA but not by IL-1, suggesting that IL-1 induction of PGHS-2 mRNA is not dependent on the protein kinase C pathway. Although FSK alone had little effect, it enhanced induction of PGHS-2 mRNA by IL-1. PGHS-1 was constitutively expressed and showed little change with treatment. In summary, we show that IL-1 is a potent inducer of PGHS-2 expression and PGE2 production in human osteosarcoma cells as well as in osteoblastic cells derived from normal human bone.
The Tromsø Study: Physical Activity and the Incidence of Fractures in a Middle-Aged Population
Authors: Joakimsen Ragnar M. , Fønnebø Vinjar , Magnus Jeanette H. , Størmer Jan , Tollan Anne , Søgaard Anne Johanne 
Published: April 2006

Abstract
We have studied the relation of occupational and recreational physical activity to fractures at different locations. All men born between 1925 and 1959 and all women born between 1930 and 1959 in the city of Tromsø were invited to participate in surveys in 1979–1980 and 1986–1987 (The Tromsø Study). Of 16,676 invited persons, 12,270 (73.6%) attended both surveys. All nonvertebral fractures (n = 1435) sustained from 1988 to 1995 were registered in the only hospital in the area. Average age in the middle of the follow-up period (December 31, 1991) was 47.3 years among men and 45.1 years among women, ranging from 32 to 66 years. Fracture incidence increased with age at all locations among women, but it decreased with or was independent of age among men. Low-energetic fractures constituted 74.4% of all fractures among women and 55.2% among men. When stratifying by fracture location, the most physically active persons among those 45 years or older suffered fewer fractures in the weight-bearing skeleton (relative risk [RR] 0.6, confidence interval [CI] 0.4–0.9, age-adjusted), but not in the non–weight-bearing skeleton (RR 1.0, CI 0.7–1.2, age-adjusted) compared with sedentary persons. The relative risk of a low-energetic fracture in the weight-bearing skeleton among the most physically active middle-aged was 0.3 (CI 0.1–0.7) among men and 0.9 (CI 0.4–1.8) among women compared with the sedentary when adjusted for age, body mass index, body height, tobacco smoking, and alcohol and milk consumption. It seems that the beneficial effect on the skeleton of weight-bearing activity is reflected also in the incidence of fractures at different sites.
Treatment with the Oral Growth Hormone Secretagogue MK-677 Increases Markers of Bone Formation and Bone Resorption in Obese Young Males
Authors: Svensson J. , Ohlsson C. , Jansson J.-O. , Murphy G. , Wyss D. , Krupa D. , Cerchio K. , Polvino W. , Gertz B. , Baylink D. , Mohan S. , Bengtsson B.-Å. 
Published: April 2006

Abstract
The effect of 2 months of treatment with the oral growth hormone (GH) secretagogue MK-677 on markers of bone metabolism was determined in healthy obese male subjects. This was a randomized, double-blind, parallel, placebo-controlled study. Twenty-four healthy obese males, 19–49 years of age, with body mass index &gt; 30 kg/m2 were treated with MK-677 (25 mg/day; n = 12) or placebo (n = 12) for 8 weeks. MK-677 increased markers of bone formation; a 23% increase in the carboxy-terminal propeptide of type I procollagen levels and a 28% increase in procollagen III peptide levels were seen with as little as 2 weeks of MK-677 treatment (p &lt; 0.01 and p = 0.001 vs. placebo, respectively) while a 15% increase in serum levels of osteocalcin was not detected until 8 weeks of treatment (p &lt; 0.01 vs. placebo). Markers of bone resorption were induced within 2 weeks of treatment with MK-677; serum levels of the carboxy-terminal cross-linked telopeptide of type I collagen were increased 26% at 8 weeks (p = 0.001 vs. placebo), and urine hydroxyproline/creatinine and calcium/creatinine ratios at 8 weeks were increased by 23% (p &lt; 0.05 vs. placebo) and 46% (p &lt; 0.05 vs placebo), respectively. MK-677 increased serum insulin-like growth factor binding protein-5 (IGFBP-5) by 43–44% after 2–8 weeks of treatment (p &lt; 0.01 vs. placebo). Serum IGFBP-4 was increased by 25% after 2 weeks of treatment (p &lt; 0.001 vs. placebo) but no significant change from baseline was observed after 8 weeks of treatment. Plasma interleukin-6 was not significantly changed by active treatment. In conclusion, short-term treatment of healthy obese male volunteers with the GH secretagogue MK-677 increases markers of both bone resorption and formation. Large increases in serum levels of IGF-I and IGFBP-5 and a transient increase in serum IGFBP-4 were found. Future long-term studies are needed to investigate if prolonged treatment with MK-677 increases bone mass.
Hormonal Predictors of Bone Loss in Elderly Women: A Prospective Study
Authors: Stone Katie , Bauer Douglas C. , Black Dennis M. , Sklarin Peter , Ensrud Kristine E. , Cummings Steven R. ,   FOR THE STUDY OF OSTEOPOROTIC FRACTURES RESEARCH GROUP
Published: April 2006

Abstract
To test the hypotheses that baseline concentrations of sex steroids, sex hormone binding globulin (SHBG), and calciotropic hormones predict rates of bone loss in elderly women, sera were stored at −190°C, and calcaneal bone mineral density (BMD) was measured in 9704 community-dwelling white women aged 65 and over (1986–1988). Hip BMD was measured 2 years later (1990). Repeat measurements of calcaneal and hip BMD were obtained in 1993–1994, after 5.7 and 3.5 years of follow-up, respectively. In 1994, sera were assayed for circulating hormone levels in random subcohorts of 231 and 218 women who did not report current use of hormone replacement therapy at baseline. Lower levels of endogenous estrogens and higher SHBG concentrations were associated with more rapid subsequent bone loss from both the calcaneus and hip. After adjusting for age and weight, women with high SHBG levels (highest quartile ≥ 2.3 μg/dl) experienced an average of 2.2% (95% confidence interval = 1.6%, 2.9%) calcaneal bone loss per year compared with 1.2% (0.7%, 1.2%) among women with low SHBG concentrations (lowest quartile &lt; 1.1 μg/dl; p &lt; 0.01). This association was independent of concentrations of other sex hormones. Women with estradiol levels ≥ 10 pg/ml averaged only 0.1% (−0.7%, 0.5%) annual hip bone loss while women with levels below 5 pg/ml averaged 0.8% (0.3, 1.2) hip bone loss per year. Lower 25-hydroxyvitamin D levels were associated with increased hip but not calcaneal bone loss. Levels of parathyroid hormone, 1,25-dihydroxyvitamin D, and calcium were not significantly associated with bone loss from the calcaneus or hip.
Urinary Ovarian and Gonadotropin Hormone Levels in Premenopausal Women with Low Bone Mass
Authors: Sowers Maryfran , Randolph John F. , Crutchfield Mary , Jannausch Mary L. , Shapiro Brahm , Zhang Bin , La Pietra Maggie 
Published: April 2006

Abstract
We hypothesized that lower ovarian and gonadotropin hormone concentrations would be associated with lower levels of peak bone mineral density (BMD) in apparently normally menstruating women who did not exercise intensively and did not report anorexia or bulimia. This hypothesis was evaluated using a case-with-control study design (n = 65) which was nested within a population-based longitudinal study of peak bone mass (Michigan Bone Health Study) with annual assessment in women aged 25–45 years (n = 582). Cases were 31 premenopausal women with BMD of the lumbar spine, femoral neck, and total body less than the 10th percentile of the distribution, where controls were 34 premenopausal women with BMD between the 50th and 75th percentile. BMD was measured by dual-energy X-ray absorptiometry. In addition to their annual measurements, these 65 participants collected first-voided morning urine specimens daily through two consecutive menstrual cycles. The urine from alternating days of this collection was analyzed for estrone-3-glucuronide (E1G), pregnanediol glucuronide (PdG), testosterone, and follicle-stimulating hormone by radioimmunoassay and these values adjusted for daily creatinine excretion levels. Additionally, analyses of daily urine specimens for luteinizing hormone (uLH) was undertaken to better characterize the possible uLH surge. Cases had significantly lower amounts of E1G (p = 0.009) and PdG (p = 0.002) than did controls, whether amounts were characterized by a mean value, the highest value, or the area under the curve, and after statistically controlling for body size. Further, when B-splines were used to fit lines to the E1G and PdG data across the menstrual cycle, the 95% confidence intervals (CIs) about the line for the controls consistently excluded and exceeded the 95% confidence bands for the cases in the time frame associated with the luteal phase in ovulatory cycles. Likewise, 95% CIs for the LH surge in controls exceeded the fitted line for cases around the time associated with the LH surge. The cases and controls were not different according to dietary intake (energy, protein, calcium), family history of osteoporosis, reproductive characteristics (parity, age at menarche, age of first pregnancy), follicular phase serum hormone levels, calciotropic hormone levels, or by evidence of perimenopause. We conclude that these healthy, menstruating women with BMD at the lowest 10th percentile from a population-based study had significantly lower urinary sex steroid hormone levels during the luteal phase of menstrual cycles as compared with hormone levels in premenopausal women with BMD between the 50th and 75th percentile of the same population-based study, even after considering the role of body size. These data suggest that subclinical decreases in circulating gonadal steroids may impair the attainment and/or maintenance of bone mass in otherwise reproductively normal women.
Effect of Combination Treatment with a Vitamin D Analog (OCT) and a Bisphosphonate (AHPrBP) in a Nude Mouse Model of Cancer-Associated Hypercalcemia
Authors: Endo Koichi , Katsumata Kyoko , Iguchi Haruo , Kubodera Noboru , Teramoto Tamio , Ikeda Kyoji , Fujita Toshiro , Ogata Etsuro 
Published: April 2006

Abstract
Hypercalcemia represents one of the important paraneoplastic syndromes affecting morbidity and mortality of cancer patients. We and others have demonstrated that vitamin D analogs with little calcemic activities suppress the transcription of the parathyroid hormone-related peptide (PTHrP) gene, a major humor responsible for cancer hypercalcemia, and thereby prevent the development of hypercalcemic syndrome. The present study was undertaken: to compare the therapeutic efficacy of a vitamin D analog, 22-oxa-1,25-dihydroxyvitamin D3 (OCT), and a bisphosphonate (disodium 3-amino-1-hydroxypropylidene-1,1-bisphosphonate pentahydrate [AHPrBP]), an inhibitor of osteoclastic bone resorption, on cancer-induced hypercalcemia; and to see if the effect could be enhanced by combination treatment, using a nude mouse model implanted with a human pancreas carcinoma (FA-6). After a single intravenous administration, OCT (5 μg/kg of body weight [BW]) was as effective as AHPrBP (10 mg/kg of BW) in lowering blood ionized calcium levels in tumor-bearing nude mice, and their combination further enhanced the therapeutic effect. Although AHPrBP lost its efficacy after repeated injections, OCT was still effective after the third administration. The therapeutic effect of OCT in cancer hypercalcemia was observed in four other human tumors, including another pancreas carcinoma (PAN-7), two squamous cell carcinomas of the lung (KCC-C1 and LC-6), and a squamous carcinoma of the pharynx (PHA-1), all of which elaborated PTHrP into the circulation. Treatment with OCT resulted in a decrease in circulating PTHrP levels by approximately 50% in two representative models. However, the mechanism underlying the antihypercalcemic effect of OCT seemed complex, involving inhibition of PTHrP production, suppression of excessive bone resorption, and an antitumor activity. OCT also markedly inhibited the body weight loss with tumor growth, while AHPrBP, which exhibited a similar antihypercalcemic effect, was less effective than OCT in preventing cachexia. The anticachectic activity of their combination did not exceed that of OCT alone, suggesting a hypercalcemia-dependent as well as an independent mechanism of cancer cachexia. It is concluded that OCT may be useful, either as a single agent or in combination with bisphosphonates, for the treatment of cancer-associated hypercalcemia and cachexia.
An Sp1 Binding Site Polymorphism in the COLIA1 Gene Predicts Osteoporotic Fractures in Both Men and Women
Authors: Langdahl Bente L. , Ralston Stuart H. , Grant Struan F. A. , Eriksen Erik F. 
Published: April 2006

Abstract
Genetic factors play an important role in the pathogenesis of osteoporosis, and recent studies have shown that a polymorphic Sp1 binding site in collagen type I α1 (COLIA1) gene is associated with bone mass and vertebral fractures in women from the U.K. Information on the predictive value of the COLIA1 Sp1 polymorphism in other populations is limited, however, and no studies have yet been performed in osteoporotic males. In view of this, we analyzed COLIA1 genotypes in relation to bone density and biochemical markers of bone turnover and the presence of osteoporotic fractures in a case-control study of Danish men and women. COLIA1 genotype was determined by polymerase chain reaction analysis of genomic DNA extracted from peripheral blood samples and related to bone mass, biochemical markers of bone turnover, and the presence of fracture in a study of 375 osteoporotic vertebral fracture patients and normal controls. There was no significant effect of COLIA1 genotype on bone mass or biochemical markers when data from the control group (n = 195) and fracture group (n = 180) were analyzed separately. However, the genotype distribution was significantly different in the fracture cases compared with age-matched controls (χ2 = 16.48, n = 249, p = 0.0003) due mainly to over-representation of the ss genotype in the fracture patients (14.3% vs. 1.4%), equivalent to an odds ratio for vertebral fracture of 11.83 (95% confidence interval 2.64–52.97) in those with the ss genotype. Similar differences in genotype distribution between osteoporotic patients and controls were observed in both men (χ2 = 11.52, n = 95, p = 0.0032, OR = 2.04) and women (χ2 = 6.90, n = 154, p = 0.032, OR = 1.37). In keeping with the above, logistic regression analysis showed that the ss genotype was an independent predictor of osteoporotic fracture (p = 0.028). This study confirms that the COLIA1 Sp1 polymorphism is significantly associated with osteoporotic vertebral fractures. The association is seen in both men and women, and the effect on fracture risk appears to be partly independent of bone mineral density. Our results raise the possibility that genotyping at the Sp1 site could be of clinical value in identifying individuals at risk of osteoporotic fractures in both genders.
Thyroid Hormone Inhibits Growth and Stimulates Terminal Differentiation of Epiphyseal Growth Plate Chondrocytes
Authors: Ishikawa Yoshinori , Genge Brian R. , Wuthier Roy E. , Wu Licia N. Y. 
Published: April 2006

Abstract
As a continuation of our studies on mineralization in epiphyseal growth plate (GP) chondrocyte cultures, the effects of tri-iodothyronine (T3) in both β-glycerophosphate-containing, serum-free (HL-1) and β-glycerophosphate-free, serum-containing medium (DATP5) were studied. The GP cells responded to T3 in a serum-, stage-, and dosage-dependent manner. Added at graded levels (0.1–10.0 nM) to preconfluent cultures (from day 7) in both HL-1 and DATP5, T3 caused progressive decreases in protein, collagen, and DNA synthesis but increased mineral deposition. In postconfluent cultures, these effects of T3 were generally muted. In preconfluent cultures, proteoglycan (PG) levels were not significantly affected in DATP5, although in HL-1 they were decreased by ∼50%. In postconfluent cultures, T3 increased PG levels in DATP5 but had no effect in HL-1. In HL-1, alkaline phosphatase (ALP) activity was progressively increased by 200–500% in both pre- and postconfluent cultures. In DATP5 in preconfluent cultures, T3 initially stimulated but later suppressed ALP; in postconfluent cultures, T3 also transiently increased ALP but did not suppress activity upon longer exposure. The inhibitory effects of T3 on protein, PG, and DNA levels of GP chondrocytes suggest that in vivo its effects on bone growth must occur primarily after cellular proliferation. Apparently by binding to the 50 kDa thyroxine-binding globulin, which cannot penetrate the PG barrier, accessibility of T3 to GP chondrocytes is limited until the time of vascular penetration when its stimulatory effects on ALP and mineral deposition become critical for continued bone development.