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)

Genetic factors play an important role in determining bone mass and several genes are involved in this process. Interleukin-6 (IL-6) is a candidate gene for regulation of bone mineral density (BMD) and it has been suggested recently that novel IL-6 -174 G/C allelic variants may be associated with peak BMD in young men and with bone resorption in elderly women. In this study, we assessed the relationships between IL-6 gene polymorphism, peak BMD, rate of postmenopausal BMD loss, and bone turnover in women. BMD was measured by dual-energy X-ray absorptiometry in 255 healthy premenopausal women, aged 31-57 years. BMD loss at the forearm was measured over 4 years in 298 healthy untreated postmenopausal women, 50-88 years (mean 64 years). We also measured levels of serum osteocalcin, bone alkaline phosphatase, and N-propeptide of type I collagen for bone formation and three markers of bone resorption, including urinary and serum C-terminal cross-linking telopeptide of type I collagen and urinary N-terminal telopeptide of type I collagen, in both pre- and postmenopausal women at baseline. In premenopausal women we found a significant association between IL-6 genotypes and BMD at the whole body (analysis of variance [ANOVA], p = 0.03), femoral neck (p = 0.03), trochanter (p = 0.014), Ward's triangle (p = 0.03), and total hip (p = 0.006), with subjects having the CC genotype showing 3%-7% higher BMD levels than their GG counterparts. However, after matching women with CC and GG genotypes for body height the differences decreased (2%-4%), and were no longer significant (p = 0.10-0.23). In postmenopausal women the mean rate of loss at the ultradistal radius was significantly associated with IL-6 genotypes (ANOVA, p = 0.049), with women having the CC genotype showing a significantly greater rate of bone loss (p < 0.05) compared with their GC and GG counterparts. After adjustment for weight changes, the difference in the rate of ultradistal radius bone loss between genotypes decreased and was not significant (p = 0.06 for CC vs. GG). A similar trend was observed for distal radius bone loss (p = 0.10, ANOVA), but not for the middle radius. We found no significant association between genotypes, bone turnover markers in premenopausal women, and either bone turnover or BMD in postmenopausal women. We conclude that this new functional IL-6 polymorphism was weakly associated with level of peak BMD and the rate of forearm trabecular postmenopausal bone loss in this cohort of healthy French women. IL-6 genotypes accounted only for a small proportion of the interindividual variation of both peak BMD and rate of bone loss and were not significant after adjustment for height and changes in body weight, respectively, suggesting that part of the effect may have been due to the differences in body size. Larger long-term studies are necessary to assess adequately the relationships between IL-6 genotype, rate of bone loss, and risk of fracture.
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PMID:Association between a functional interleukin-6 gene polymorphism and peak bone mineral density and postmenopausal bone loss in women: the OFELY study. 1211 Apr 11

A polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) has recently been associated with bone mineral density (BMD) in postmenopausal Japanese women. It is not known whether this effect is also present in European populations and whether it is caused by lower peak bone mass or accelerated postmenopausal bone loss. MTHFR genotyping was done in 1748 healthy postmenopausal Danish women participating in a prospective study of risk factors for osteoporosis. At the time of enrollment, 3-24 months after last menstrual period, the less prevalent genotype (TT, 8.7% of the population) was associated with significantly lower BMD at the femoral neck (ANOVA, p < 0.05), total hip (p < 0.01), and spine (p < 0.05 adjusted for lifestyle covariates, p = 0.06 without adjustment). The mean difference was between 0.1 and 0.3 SD, depending on measurement site. MTHFR genotype added significantly to prediction of BMD by weight and age. Fracture incidence was increased more than 2-fold in subjects with the TT genotype (risk ratio [RR], 2.6; 95% CI 1.2-5.6). This remained significant when the Cox analysis was controlled for BMD (RR, 2.4; 95% CI 1.1-5.2). No differences in serum osteocalcin, bone-specific alkaline phosphatase, and 25-OH-vitamin D were found between genotypes. The response to hormone replacement therapy (HRT) did not differ, but the association of the TT genotype with reduced BMD was maintained at the total hip after 5 years of HRT. The MTHFR TT genotype is associated with low BMD and increased fracture incidence in early postmenopausal women.
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PMID:A common methylenetetrahydrofolate reductase (C677T) polymorphism is associated with low bone mineral density and increased fracture incidence after menopause: longitudinal data from the Danish osteoporosis prevention study. 1267 33

The aim of the PREVOS study (PREVention Of early postmenopausal bone loss by Strontium ranelate) and the STRATOS study (STRontium Administration for Treatment of OSteoporosis) was to determine the minimum dose at which strontium ranelate (SR) is effective in, respectively, the prevention of bone loss in early postmenopausal nonosteoporotic women and the treatment of postmenopausal vertebral osteoporosis. Both studies were randomized, double-blind, placebo-controlled, dose-finding studies in parallel groups and lasted 2 years. In the PREVOS study, 160 early postmenopausal women were randomized to receive placebo, SR 125 mg/day, 500 mg/day or 1 g/day. In the STRATOS study, 353 osteoporotic postmenopausal women with at least one previous vertebral fracture and a lumbar T-score <-2.4 were randomized to receive placebo, SR 500 mg/day, 1 g/day or 2 g/day. In both studies, the primary efficacy parameter was lumbar bone mineral density (BMD) measured by dual-energy X-ray absorptiometry. Secondary efficacy criteria included incidence of new vertebral deformities (in the STRATOS study only) and biochemical markers of bone metabolism. In the PREVOS study, the increase in lumbar BMD from baseline in the 1 g/day group (+5.53%) was significantly different from the decrease in the placebo group ( p<0.001). In the STRATOS study, the annual increase in lumbar BMD in the 2 g/day group (+7.3% per year) was significantly higher than in the placebo group ( p<0.001). There was a significant reduction in the number of patients experiencing new vertebral deformities in the second year of treatment in the 2 g/day group (relative risk: 0.56; 95% confidence interval: 0.35, 0.89). In both studies, there was a significant increase in the bone formation marker (bone alkaline phosphatase) in the higher-dose group. Urinary excretion of the marker of bone resorption (cross-linked N-telopeptide) was lower with SR than with placebo in the STRATOS study. SR was very well tolerated in both studies. The minimum dose at which SR is effective in preventing bone loss in early postmenopausal nonosteoporotic women and in the treatment of postmenopausal osteoporosis is 1 g/day and 2 g/day, respectively.
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PMID:Strontium ranelate phase 2 dose-ranging studies: PREVOS and STRATOS studies. 1586 11

Postmenopausal osteoporosis is preventable. An increasing number of antiresorptive therapies including estrogen, selective estrogen receptor modulators (the so-called designer estrogens), bisphosphonates and calcitonins are now available as treatment options for osteoporosis. These agents reduce the level of bone turnover and consequently slow or arrest bone loss and decrease the risk of fracture. However, these therapies are only effective if they are taken as prescribed. Unfortunately, most women who initiate antiresorptive therapy are unwilling or unable to make a long-term commitment to maintain such therapy. The test for biochemical markers of bone turnover can be used to confirm a biochemical response of bone within 3-6 months of initiating therapy, far sooner than the 2 years required for bone density testing. Such information incorporates a timely assessment of the woman's physiologic response with therapeutic compliance. A test result indicating the expected response to treatment may motivate some patients to remain compliant and maintain the therapy for an extended period of time. Bone turnover markers with demonstrated efficacy in monitoring the reduction of bone turnover induced by antiresorptive therapies include bone-specific alkaline phosphatase and osteocalcin (bone formation markers), and free deoxypyridinoline, N-telopeptide and C-telopeptide (bone resorption markers).
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PMID:Monitoring antiosteoporotic treatment of postmenopausal women using biochemical markers of bone turnover. 1297 83

Raloxifene, a nonsteroidal selective estrogen receptor modulator (SERM), increases bone mineral density (BMD), decreases biochemical markers of bone turnover, and prevents incident vertebral fractures in postmenopausal women, while sparing the breast and endometrium from the undesirable stimulation caused by estrogen. How the long-term beneficial effects of raloxifene on bone turnover, as assessed by bone histomorphometry, compare with hormone replacement therapy (HRT) and placebo are not known. We studied 66 healthy postmenopausal women (age 55 to 75 years, mean 63 years) who were randomized to either raloxifene 150 mg/day, HRT (Premarin 0.625 mg/day, and Provera 2.5 mg/day), or placebo for 1 year. All women received 1-1.5 g of calcium/day. Following double tetracycline labeling, transiliac bone biopsies were obtained at baseline and 1 year and analyzed for changes in histologic indexes of bone remodeling on the cancellous surface as well as at the endocortical subdivision of the endosteal envelope, the location of the greatest fraction of postmenopausal bone loss. BMD and biochemical markers of bone turnover were also determined at baseline and 1 year. Four paired biopsies were obtained in the HRT group, six in the raloxifene group, and five in the placebo group. The frequency of remodeling events on cancellous bone and rate of bone formation in both cancellous and endocortical bone increased in the placebo group, while these measurements decreased in both drug treatment groups. Using analysis of mean percentage changes, when compared with the placebo group, these changes were significantly different for both raloxifene and HRT treatment groups (p<0.02). In all subjects, the bone was lamellar with discrete tetracycline labels and there was no evidence of marrow fibrosis or abnormal bone cells. BMD increased from baseline at the lumbar spine (p<0.05 in the HRT group) and in the total body (p<0.05 for both raloxifene and HRT). Compared with that of the raloxifene group, the increase in BMD was greater in the HRT group at the lumbar spine but not in the total body. Serum bone alkaline phosphatase, serum osteocalcin, and urine C-terminal cross-linking telopeptide of type I collagen significantly decreased (p<0.05) in both active treatment groups, changes significantly different from those seen with placebo. Overall, these results support the hypothesis that raloxifene preserves bone mass by reducing the elevated bone turnover found in postmenopausal women receiving placebo, by mechanisms similar to those operative in postmenopausal women receiving HRT.
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PMID:Effects of raloxifene, hormone replacement therapy, and placebo on bone turnover in postmenopausal women. 1461 Jun 42

Tob (transducer of erbB2) is a member of antiproliferative family proteins and acts as a bone morphogenic protein inhibitor as well as a suppressor of proliferation in T cells, which have been implicated in postmenopausal bone loss. To determine the effect of Tob deficiency on estrogen deficiency-induced bone loss, we analyzed bone metabolism after ovariectomy or sham operation in Tob-deficient mice. Ovariectomy in WT mice decreased trabecular bone volume and bone mineral density (BMD) as expected. In Tob-deficient mice, ovariectomy reduced bone volume and BMD. However, even after ovariectomy, both trabecular bone volume and BMD levels in Tob-deficient bone were comparable to those in sham-operated WT bones. Bone formation parameters (mineral apposition rate and bone formation rate) in the ovariectomized Tob-deficient mice were significantly higher than those in the ovariectomized WT mice. In contrast, the ovariectomy-induced increase in the bone resorption parameters, osteoclast surface, and osteoclast number was similar between Tob-deficient mice and WT mice. Furthermore, in ex vivo nodule formation assay, ovariectomy-induced enhancement of nodule formation was significantly higher in the bone marrow cells from Tob-deficient mice than in the bone marrow cells from ovariectomized WT mice. Both Tob and estrogen signalings converge at bone morphogenic protein activation of alkaline phosphatase and GCCG-reporter gene expression in osteoblasts, revealing interaction between the two signals. These data indicate that Tob deficiency prevents ovariectomy-induced bone loss through the superenhancement of osteoblastic activities in bone and that this results in further augmentation in the bone formation rate and the mineral apposition rate after ovariectomy in vivo.
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PMID:Tob deficiency superenhances osteoblastic activity after ovariectomy to block estrogen deficiency-induced osteoporosis. 1510 Apr 14

To examine a potential role for soybean phytoestrogens in postmenopausal bone loss, twenty-four 12-week-old Sprague-Dawley rats were divided randomly into 4 groups and given controlled diets for 16 weeks. The treatment groups were as followed: sham operated, ovariectomized (OVX) control, OVX + isoflavone extract (6.25 g/kg), and OVX + 17beta-estradiol (4 mg/kg). OVX treatments reduced femoral and fourth lumbar vertebral bone density and mineral content (p<0.01), decreased uterine weight (p<0.01), accelerated body weight increases (p<0.05), and increased the activities (p<0.01) of both serum alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP). Supplementation with isoflavone prevented the losses of bone density and mineral content caused by OVX (p<0.01). Although both isoflavone and 17beta-estradiol exhibited similar bone-sparing ability on the OVX-induced bone loss, the effect of isoflavone was not the same as that of 17beta-estradiol on the serum ALP and TRAP, body weight increase, and uterine weight change. We concluded that dietary supplementation with soybean isoflavone can prevent postmenopausal bone loss via a different mechanism of estrogen in OVX rats.
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PMID:Evaluation of the preventive effect of isoflavone extract on bone loss in ovariectomized rats. 1517 Jan 7

Bone mass is maintained when low-dose ethinylestradiol is used in combination with the new progestogen drospirenone as an oral contraceptive, making a regimen of drospirenone combined with 17beta-estradiol an attractive option for hormone replacement therapy (HRT) in postmenopausal women. Drospirenone is a novel progestogen, more closely related to endogenous progesterone in its pharmacological properties than other progestogens available; in combination with estrogen, drospirenone can closely mimic the premenopausal hormonal balance. In a phase II/III double-blind, placebo-controlled, randomized trial, three different doses of drospirenone plus low-dose 17beta-estradiol were compared with placebo, in order to determine their effects on bone density. Of 240 healthy postmenopausal women aged 45-65 years who enrolled, 180 completed the 2-year prospective study. Treatment groups received 1 mg 17beta-estradiol combined with 1, 2 or 3 mg drospirenone daily or placebo. Bone mineral densities at the lumbar spine, hip and total body and markers of bone turnover were measured at 1, 3, 6, 12, 18 and 24 months. In the pooled HRT groups, the bone mineral density at the lumbar spine, hip and total body increased by 7%, 4% and 3%, respectively, compared with placebo (all p < 0.001). Markers of bone turnover in HRT groups all decreased accordingly (serum osteocalcin 52%, serum bone-specific alkaline phosphatase 36%, serum CrossLaps 67% and urinary CrossLaps 75% from baseline; all p < 0.001). The combination of 17beta-estradiol with drospirenone offers a safe and effective medication for decreasing bone turnover and preventing postmenopausal bone loss in postmenopausal women.
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PMID:Effects of drospirenone/estrogen combinations on bone metabolism. 1620 54

This study investigated whether soy isoflavone intake, with or without estrogen treatment, can reduce postmenopausal bone loss, and whether soy isoflavones can be an alternative for estrogen replacement therapy using a postmenopausal osteoporotic rat model in which ovariectomized female rats were fed a low calcium, high fat diet. Nine-week-old female Sprague-Dawley rats were ovariectomized and then fed low (0.1%) calcium diets with or without soy isoflavone supplementation (80 or 160 ppm) for 6 weeks. Some ovariectomized rats were fed the same diets but also injected with estrogen (10 microg/kg of body weight) subcutaneously. Serum calcium and phosphate levels were normal in all rats. Serum alkaline phosphatase activities were not affected by the treatments. Serum tartrate-resistant acid phosphatase activities and urinary hydroxyproline levels were not different between experimental groups. Bone mineral (calcium and phosphorus) contents were increased in the rats supplemented with 80 ppm soy isoflavone or the rats treated with only estrogen without soy isoflavone. Therefore, the effect of 80 ppm soy isoflavone supplementation was the same as estrogen injection, but there was no beneficial effect from combining soy isoflavones and estrogen injections. When 160 ppm soy isoflavone was used, the benefits were lessened or disappeared altogether. These results suggest that appropriate soy isoflavone supplementation prevents postmenopausal bone loss without estrogen injection and may have efficacy as an alternative to estrogen therapy.
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PMID:Effects of soy isoflavone and/or estrogen treatments on bone metabolism in ovariectomized rats. 1637 53

Hormone replacement therapy is effectively used to prevent postmenopausal bone loss. Variation in response to the therapy is, however, frequently seen. In addition, the direct effects of sex steroids on isolated human bone marrow stromal cells have been reported to vary depending on the donor, but the biological mechanisms are not understood. The aim of this study was to investigate the effects of 17beta-estradiol (E2) and testosterone in human-bone-marrow-derived mesenchymal stem cell (MSC) cultures from both female and male donors of various ages. The osteoblast differentiation capacity and activity of the MSCs were quantified in vitro by measuring alkaline phosphatase activity and calcium deposition. We show here that also the osteoblast responses of MSCs to sex hormones vary widely depending on the donor. When the results from all donors were analyzed together, treatment with E2 increased calcium deposition significantly by MSCs of both sexes but ALP activity only in the male MSCs. Testosterone had no effect on ALP activity nor calcium deposition in either sex. To further characterize the individual variation, we investigated estrogen receptor alpha PvuII restriction site polymorphism with PCR. Restriction fragment-length polymorphism was assigned as P or non-P, P signifying the absence of the restriction site. Our results indicate that higher basal osteoblast differentiation capacity of MSCs is associated with the presence of the P allele in females, whereas higher response to sex steroids treatment is associated with the non-P allele. These results could help explain the contradictory effects of E2 on osteoblasts in vitro and might also provide new insights to understanding the differences in responses to hormone replacement therapy.
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PMID:Estrogen receptor alpha genotype confers interindividual variability of response to estrogen and testosterone in mesenchymal-stem-cell-derived osteoblasts. 1678 20


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