Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bone loss is accelerated in elderly men. Little is known about the pathophysiology of senile bone loss or about the role played by relative sex steroid deficiency in the determination of bone turnover in elderly men. In a population-based sample of 283 healthy, ambulatory men, aged 71-86 years, we sought to determine whether lower bone mineral density (BMD; using dual-energy X ray absorptiometry at the hip and the forearm) is associated with higher bone turnover, and we assessed the impact of sex steroid status on bone turnover. Indices of bone formation, serum osteocalcin (s-Oc), and bone-specific alkaline phosphatase (s-bAP) and indices of bone resorption, serum and urinary telopeptide of type I collagen (s-CTx and u-CTx), and urinary free deoxypyridinoline (u-Dpd) were intercorrelated (r = 0.29-0.76, p < 0.001). Bone turnover indices were negatively associated with BMD (r = -0.17 to -0.34, p < 0.01). In univariate analyses, there was a trend toward weak negative associations of bone turnover markers with serum free testosterone (FT), significant only for s-Oc and s-CTx (r = -0.16 and -0.14, p < 0.01), and with serum free estradiol (FE(2)), significant only for u-CTx and s-CTx (r = -0.18 and -0.19; p < 0.01). The lower quartile for FE(2) was associated with higher values of u-CTx (p = 0.003) and s-CTx (p < 0.001). However, in multivariate models, for the individual markers of bone turnover a negative association between estradiol (E(2)) or FE(2) and s-CTx was the only remaining (marginally) significant association (p < 0.05) for the relationship between sex steroids and any of the bone turnover indices assessed. In community-dwelling men age >70 years, bone turnover rate, as determined by biochemical markers, is a significant negative determinant of prevalent BMD. However, the findings do not support the view that relative differences in sex steroid status, as observed among healthy elderly men, have a major impact on bone turnover.
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PMID:Inverse association between bone turnover rate and bone mineral density in community-dwelling men >70 years of age: no major role of sex steroid status. 1155 74

The aim of this study was to evaluate bone mineral density and some markers of bone metabolism (alkaline phosphatase activity, osteocalcin concentration, deoxypirydinoline excretion), as well as the influence of physical activity and dietary calcium supplementation on bone density and bone metabolism in boys with a constitutional delay of growth and puberty (CDGP), in relation to calendar age, bone age and pubertal stage. The study was done in 41 boys aged 8-18 years with CDGP diagnosed on the basis of family history and typical pattern of growth, with prior exclusion of hormonal and non-hormonal causes of height deficiency. According to Tanner's criteria, boys were assigned to 4 groups corresponding to 4 stages of puberty (Tab. 1). Total body (total BMD) and lumbar spine (L2L4 BMD) bone mineral density were obtained using DEXA densitometry. The activity of alkaline phosphatase (AP) and serum osteocalcin (OC) concentration served as markers of bone formation. 24-h urinary deoxypirydinoline (DPD) excretion was a marker of bone resorption. Using a questionnaire, daily dietary calcium intake and physical activity were established. A positive correlation between calendar age, total BMD and L2L4 BMD was found (R = 0.70 and R2 = 0.49; R = 0.72 and R2 = 0.51; p < 0.001, respectively). Bone age was positively correlated with total BMD and L2L4 BMD (for both correlations R = 0.68, R2 = 0.47; p < 0.001). Total BMD adjusted for calendar age revealed osteoporosis in 4 cases (9.7%), osteopenia in 19 cases (46.3%) and normal bone density in 18 cases (43.9%). After adjustment of BMD to bone age, 2 boys (4.9%) were diagnosed with osteoporosis, 9 (21.9%) with osteopenia, and 30 (73.2%) with normal bone density. L2L4 BMD adjusted for calendar age showed osteoporosis in 6 cases (14.6%), osteopenia in 21 cases (51.2%) and normal density in 14 cases (34.2%). After adjustment of BMD to bone age, 3 boys (7.3%) were diagnosed with osteoporosis, 10 (24.4%) with osteopenia, and 28 (68.3%) with normal bone density. A significant correlation between stage of puberty, total BMD (p < 0.045) and L2L4 BMD (p < 0.001) was found. Values for total BMD and L2L4 BMD in boys with CDGP in relation to pubertal stage are presented in Table 2. Mean AP activity, serum OC concentration, DPD excretion, dietary calcium intake and physical activity in boys at consecutive stages of puberty are presented in Table 3. No significant correlation between pubertal stage, markers of bone metabolism, daily dietary calcium intake or physical activity was found. The boys were next grouped according to level of physical activity: low (< 10 h/week) or high (> 10 h/week). Table 4 summarizes the results for both groups. No significant differences between the groups were found concerning the parameters studied. Two groups with a low (< 1.2 g) and high (> 1.2 g) dietary calcium intake were also formed. The results for both groups are presented in Table 5. A significant correlation between dietary calcium intake and total BMD (R = 0.34 and R2 = 0.11; p < 0.03) was revealed. On the basis of these results it can be concluded that BMD values in boys with CDGP should be adjusted for bone age, thus significantly limiting the diagnosis of osteoporosis and osteopenia. BMD values for these boys increase with consecutive pubertal stage, while markers of bone metabolism do not reveal significant abnormalities (markers of bone formation increase until stage IV, markers of bone resorption show fluctuating values).
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PMID:[Evaluation of bone mineral density and selected metabolic markers of bone in boys with constitutional delay of growth and puberty]. 1171 2

We studied the relationship between change in bone turnover and vertebral fracture risk during raloxifene therapy using 3-year data from the MORE trial, where 2622 of the 7705 randomized women had measurement of bone markers at baseline and after 6 and 12 months participation. Change in bone turnover was significantly related to future risk of vertebral fracture, also after adjusting for baseline vertebral fracture status and BMD. Thus, for a decrease of 9.3 pg/l in serum osteocalcin after 1 year's raloxifene therapy, the odds ratio (OR) for a new vertebral fracture during 3 years was 0.69 (0.54-0.88), p = 0.003. Similarly, for a decrease of 5.91 microg/l in serum bone alkaline phosphatase, OR was 0.75 (0.62-0.92), p = 0.005. The change in BMD over 12 and 24 months was not related to fracture risk in any of the analyses. The strongest predictor for vertebral fracture was prevalent vertebral fracture--even during therapy. The predictive value of baseline BMD was in the same order of magnitude as bone turnover change during raloxifene treatment. In conclusion, the change in bone turnover is related to fracture risk during raloxifene therapy. In contrast the change in BMD is not related to fracture risk. The strongest predictor for vertebral fracture is prevalent vertebral fracture.
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PMID:Six and twelve month changes in bone turnover are related to reduction in vertebral fracture risk during 3 years of raloxifene treatment in postmenopausal osteoporosis. 1180 44

In 12 patients (mean age, 33 +/- 13 years) with type 1 Gaucher disease (GD), we evaluated bone mass by broadband ultrasound attenuation (BUA) of the calcaneus and dual X-ray absorptiometry (DXA) of the total body, lumbar spine, and hip. In all patients, we measured serum levels of osteocalcin (OC) and bone-specific alkaline phosphatase (BAP) and urinary excretion of pyridinoline (Pyr/Cr) and deoxypyridinoline (D-Pyr/Cr) cross-links. Compared to age- and sex-matched healthy controls, patients with GD showed marked osteopenia at all measuring sites as expected. Values of BUA (67.25 +/- 15.83 dB/MHz) were also significantly reduced. OC and BAP concentrations were within the normal range. Pyr/Cr and D-Pyr/Cr were significantly higher than in controls. Calculating T- and Z scores, we found a significant correlation between the Bone Severity Score Index (BSSI) and both BUA and BMD measurements. A significant correlation was also found between pyridinoline urinary excretion and both BSSI and BUA at the calcaneus. Our data suggest that type 1 GD in adulthood is associated with increased bone resorption and that BUA at the calcaneus may be a relevant tool in the assessment of bone status in these patients.
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PMID:Bone ultrasonometry, bone density, and turnover markers in type 1 Gaucher disease. 1181 Apr 14

Strontium ranelate is composed of an organic moiety (ranelic acid) and of two atoms of stable non-radioactive strontium. In vitro, strontium ranelate increases collagen and non-collagenic proteins synthesis by mature osteoblast enriched cells. The effects of strontium ranelate on bone formation were confirmed as strontium ranelate enhanced pre-osteoblastic cells replication. The stimulation by strontium ranelate of the replication of osteoprogenitor cells and collagen as well as non-collagenic protein synthesis in osteoblasts provides substantial evidence to categorise SR ranelate as a bone forming agent. In the mouse calvaria culture system, SR ranelate induces a dose-dependent inhibition of labelled calcium release. The inhibitory effects of SR ranelate on bone resorption were close to those of salmon calcitonin. In the isolated rat osteoclast assay, a pre-incubation of bone slices with SR ranelate induced a dose-dependent inhibition of the bone resorbing activity of a treated rat osteoclast. SR ranelate also dose-dependently inhibited, in a chicken bone marrow culture, the expression of both CA II and the alpha-subunit of the vitronectin receptor. These effects showing that SR ranelate significantly affects bone resorption due to direct and/or matrix-mediated inhibition of osteoclast activity and also inhibits osteoclasts differentiation are compatible with the profile of an anti-resorptive drug. In normal rats, administration of SR ranelate induces an improvement in the mechanical properties of the humerus and/or the lumbar vertebra associated with a commensurate increase in bone dimension, shaft and volume. This was not related to any change in the stiffness, suggesting the absence of a mineralisation defect. After oral administration of SR ranelate in humans, the absolute bio-availability of SR ranelate is 27 % after a dose of 2g is given as sachets. The simultaneous intake of SR ranelate and calcium remarkably reduces the bio-availability of SR. SR ranelate was administered in 160 early postmenopausal women, in a 24-month, double-blind, placebo-controlled, prospective randomized study. Daily oral dose of 125 mg, 500 mg, 1 g of SR ranelate were compared to a placebo. At the conclusion of the study, the percent variation of lumbar adjusted BMD from baseline was significantly different in the group receiving 1 g/day of SR as compared to placebo (+ 1.41 % versus 0.98 % respectively). Increase in total hip and neck BMD averages respectively 3.2 % and 2.5 %. SR ranelate does not induce any significant adverse reaction compared to those observed in women receiving a placebo for the same duration. In a phase II study, the effect of SR ranelate in postmenopausal women with vertebral osteoporotic fractures were assessed during a double-blind, placebo-controlled trial. SR ranelate (500 mg, 1 g, 2 g per day) or placebo were given to 353 Caucasian women with prevalent osteoporosis. At the conclusion of this two-year study, the annual increase in lumbar adjusted BMD of the group receiving 2 g of SR ranelate was + 2.97 %. This result was significantly different as compared to placebo. A significant decrease in pyridinium crosslinks (NTX) and an increase in bone specific alkaline phosphatase were evident after 3 and 6 months of treatment. During the second year of treatment, the dose of 2 g was associated with a 4 % reduction in the number of patient experiencing a new vertebral deformity. Bone histomorphometry showed no mineralisation defects. The same percentage of withdrawal following an adverse effect was observed for patients receiving placebo and for those receiving 2 g of strontium ranelate. Currently, strontium ranelate is further investigated in a large Phase III program that includes two extensive trials for the treatment of severe osteoporosis, one assessing SR ranelate effects on the risk of vertebral fractures (SOTI) and one evaluating the effects of SR ranelate on peripheral (non spinal) fractures (TROPOS). The primary analysis of the SOTI study, evaluating the effect of 2 g of strontium ranelate on vertebral fracture rates are expected to be released during the summer 2002.
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PMID:Strontium ranelate in osteoporosis. 1217 30

Melanocortin is the downstream mediator of leptin signaling and absence of leptin signaling in ob/ob and db/db mice revealed the enhancement of bone formation through the central regulation. While alpha-melanocyte-stimulating hormone (alphaMSH) inhibits the secretion of interleukin-1alpha and tumor necrosis factor-alpha from the inflammatory cells, alphaMSH can also enhance clonal expansion of pro B cells linked to stimulation of osteoclastogenesis. Therefore, we tested the effect of melanocortin on bones. alphaMSH analogues [(6)His]alphaMSH-ND and [(6)Asn]alphaMSH-ND were synthesized and the radio-ligand receptor binding- and cyclic AMP generating activity were analyzed in China Hamster Ovary cell line over- expressing melanocortin receptors. The EC(50) of [(6)His]alphaMSH-ND measured from melanocortin-1, 3, 4 and 5 receptors were 0.008 +/- 0.0045, 1.523 +/- 0.707, 0.780 +/- 0.405, and 250.320 +/- 42.234 nM, respectively, and the EC(50) of [(6)Asn]alphaMSH-ND were 16.8 +/- 6.94, 271.8 +/- 21.95, 8.0 +/- 1.21, and 1132.5 +/- 635.46 nM, respectively. Four weeks after the subcutaneous injection of the analogues, the body weights in the [(6)His]alphaMSH-ND and the [(6)Asn]alphaMSH-ND treated groups (346.0 +/- 20.63 g vs. 350.0 +/- 13.57 g) were lower than that of the vehicle treated group (375.8 +/- 17.31 g, p < 0.05). There was no difference in the total femoral BMD measured by dual x-ray absorptiometry among the three groups. Among the three groups, there were no differences in the total numbers of crystal violet positive- or alkaline phosphatase positive colonies, in the expression of Receptor Activator of Nuclear Factor Kappa-B ligand on the tibia and the total number of multinucleated osteoclast-like cells differentiated from primary cultured bone marrow cells. From the above results, no evidence of bone gain or loss was found after treatment of the alphaMSH analogues peripherally.
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PMID:The effect of alphaMSH analogues on rat bones. 1220 39

The aim of this study was to provide confirmation that once-weekly dosing with 70 mg of alendronate (seven times the daily oral dose) and twice-weekly dosing with 35 mg is equivalent to the 10-mg once-daily regimen and to gain more extensive safety experience with this new dosing regimen. Twelve hundred fifty-eight postmenopausal women (aged 42-95 years) with osteoporosis (bone mineral density [BMD] of either lumbar spine or femoral neck at least 2.5 SDs below peak young adult mean or prior vertebral or hip fracture) were assigned to receive oral once-weekly alendronate, 70 mg (n = 519); twice-weekly alendronate, 35 mg (n = 369); or daily alendronate 10 mg (n = 370) for a total of 2 years of double-blind experience. Mean BMD increases from baseline (95% CI) at 24 months in the once-weekly, twice-weekly, and daily treatment groups, respectively, were 6.8% (6.4, 7.3), 7.0% (6.6,7.5), and 7.4% (6.9,7.8) at the lumbar spine and 4.1% (3.8,4.5), 4.3% (3.9,4.7), and 4.3% (3.9,4.7) at the total hip. These increases in BMD as well as the BMD increases at the femoral neck, trochanter, and total body and the reductions of biochemical markers of bone resorption (urinary cross-linked N-telopeptides of type I collagen [NTx]) and bone formation (serum bone-specific alkaline phosphatase [BSAP]) were similar for the three dosing regimens. All treatment regimens were well tolerated with a similar incidence of upper gastrointestinal (GI) adverse experiences. The incidence rates of clinical fractures, captured as adverse experiences, were similar among the groups. The 2-year results confirm the conclusion reached after 1 year that once-weekly alendronate is therapeutically equivalent to daily dosing, providing patients with a more convenient dosing option that may potentially enhance adherence to therapy.
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PMID:Two-year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis. 1241 6

Abnormalities of calcium and vitamin D metabolism in cystic fibrosis (CF) are well documented. We tested the hypothesis that alterations in calcium metabolism are related to vitamin D deficiency, and that bone resorption is increased relative to accretion in patients with CF. Calcitropic hormones, electrolytes, osteocalcin (OC) and bone alkaline phosphatase (BAP), (markers of bone mineralisation), urinary deoxypyridinoline [total (t) Dpd, a marker of bone resorption] and lumbar spine bone mineral density (LS BMD), expressed as a z-score, were measured in 149 (81 M) CF and 141 (61 M) control children aged 5.3-10.99 years, adolescents aged 11-17.99 years and adults aged 18-55.9 years. Data were analysed by multiple regression to adjust for age. In patients, FEV(1)% predicted and CRP (as disease severity markers), genotype and pancreatic status (PS) were recorded. The distribution of PTH differed between groups ( P<0.0001), with CF levels both below and above the control range. 25OH vitamin D (25OHD) was not different in control and CF subjects ( P=0.06). Active hormonal vitamin D (1,25(OH)(2)D) was lower in the CF group ( P<0.0001), not explained by 25OHD or disease severity, as was serum magnesium ( P<0.0001). OC was decreased in CF adults ( P=0.004), and tDpd increased in CF adolescents ( P=0.003) and adults ( P=0.03). The ratio of OC to tDpd (a measure of bone coupling) was similar in CF and control children, but decreased in CF adolescents ( P=0.04) and adults ( P=0.02), suggesting decreased overall bone accrual in CF adolescents and uncoupling of bone balance in adults. 1,25(OH)2D was weakly correlated with OC in CF children ( r=0.43, P=0.01), and with tDpd in CF and control adolescents ( r=0.33, P=0.05 and r=0.36, P=0.02, respectively); thus there was limited evidence of association of calcitropic hormones, which had an abnormal pattern in all age groups, with bone turnover. There was no association between calcitropic hormones or bone turnover markers and LS BMD z-score. Despite vitamin D sufficiency, abnormalities of calcium metabolism and bone turnover markers were still apparent and bone accretion was decreased relative to resorption in the CF adolescent and adult groups. These changes were not fully explained by disease severity or genotype, but are consistent with reports of decreased BMD and unique bone histomorphometry in older subjects with CF.
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PMID:Abnormalities of the PTH-vitamin D axis and bone turnover markers in children, adolescents and adults with cystic fibrosis: comparison with healthy controls. 1273 Jul 64

An extract from corn germ induced a positive response in the pigeon crop sack test, used for the detection of prolactin-like substances. One of the substances extracted was identified as ferulic acid, which was reported to affect serum gonadotropin levels in ovariectomized male rats. To evaluate the effects of ferulic acid on bone loss, ovariectomized female rats of the Sprague-Dawley strain at age 35 weeks were given ferulic acid and/or 17a-ethynylestradiol daily for 8 weeks, and serum hormone levels and tibial bone mineral density were measured. In metaphysis of the tibia, which was abundant in cancellous bone and more reflective of BMD than whole tibia, the BMD was markedly reduced by ovariectomy and enhanced by the treatment with estrogen or ferulic acid in the ovariectomized rats. The treatment slightly increased the serum levels of estrogen and progesterone and alkaline phosphatase activity, which was reduced by estrogentreatment, i.e. the mechanism of bone formation by ferulic acid was suggested to be different from that by estrogens. These results indicate that ferulic acid promotes bone remodeling, leading to a predominantly osteoblastic phase, besides bone resorption by osteoclasts.
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PMID:Preventive effect of ferulic acid on bone loss in ovariectomized rats. 1292 80

Chemical mutagenesis followed by screening for abnormal phenotypes in the mouse holds much promise as a method for revealing gene function. We describe a mouse N-ethyl-N-nitrosourea (ENU) mutagenesis program incorporating a genomewide screen of dominant as well as recessive mutations affecting musculoskeletal disorders in C3H/HeJ mice. In a primary screen, progeny of one-generation dominant mutations (F(1)) and three-generation recessive (F(3)) mutations were screened at 10 weeks of age for musculoskeletal disorders using dual-energy X-ray absorptiometery (DEXA) and biochemical markers affecting bone metabolism, such as osteocalcin, type I collagen breakdown product, skeletal alkaline phosphatase, and insulin-like growth factor I (IGF-I). Abnormal phenotypes were identified as +/-3SD units different from baseline data collected from age- and sex-matched nonmutagenized control mice. A secondary screen at 16 weeks of age, which included peripheral quantitative computed tomography (pQCT) in addition to those parameters described in our primary screen, was used to confirm the abnormal phenotypes observed in the primary screen. The phenodeviant or outlier mice were progeny tested to determine whether their abnormality segregates bimodally in their offspring with the expected 1:1 or 1:3 Mendelian ratio, in dominant and recessive screens, respectively. With the above screening strategy, we were able to identify several mice with quantitative abnormalities in BMD, BMC, bone size, and bone metabolism. We have progeny tested and confirmed four outliers with low BMD, low bone size, and growth-related abnormality. Our results indicate that the magnitude of change in quantitative phenotypes in the ENU-mutagenized progeny was between 10 and 15%, and hence, the yield of outliers was dependent on the precision of the methods. So far, this ENU mutagenesis program has identified four outliers that can undergo positional cloning.
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PMID:A genomewide screening of N-ethyl-N-nitrosourea-mutagenized mice for musculoskeletal phenotypes. 1449 51


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