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)

Hypophosphatemic transgenic (tg) mice overexpressing FGF23 in osteoblasts display disorganized growth plates and reduced bone mineral density characteristic of rickets/osteomalacia. These FGF23 tg mice were used as an in vivo model to examine the relation between osteoclast polarization, secretion of proteolytic enzymes and resorptive activity. Tg mice had increased mRNA expression levels of the osteoblast differentiation marker Runx2 and mineralization-promoting proteins alkaline phosphatase and bone sialoprotein in the long bones compared to wild type (wt) mice. In contrast, expression of alpha1(I) collagen, osteocalcin, dentin matrix protein 1 and osteopontin was unchanged, indicating selective activation of osteoblasts promoting mineralization. The number of osteoclasts was unchanged in tg compared to wt mice, as determined by histomorphometry, serum levels of TRAP 5b activity as well as mRNA expression levels of TRAP and cathepsin K. However, tg mice displayed elevated serum concentrations of C-terminal telopeptide of collagen I (CTX) indicative of increased bone matrix degradation. The majority of osteoclasts in FGF23 tg mice lacked ultrastructural morphological signs of proper polarization. However, they secreted both cathepsin K and MMP-9 at levels comparable to osteoclasts with ruffled borders. Mineralization of bone matrix thus appears essential for inducing osteoclast polarization but not for secretion of osteoclast proteases. Finally, release of CTX by freshly isolated osteoclasts was increased on demineralized compared to mineralized bovine bone slices, indicating that the mineral component limits collagen degradation. We conclude that ruffled borders are implicated in acidification and subsequent demineralization of the bone matrix, however not required for matrix degradation. The data collectively provide evidence that osteoclasts, despite absence of ruffled borders, effectively participate in the degradation of hypomineralized bone matrix in rachitic FGF23 tg mice.
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PMID:Osteoclast polarization is not required for degradation of bone matrix in rachitic FGF23 transgenic mice. 1834 51

Persistent circadian rhythm of bone turnover in bone metastatic breast cancer suggests greater skeletal retention of bisphosphonates if administered in the night. We assessed differential effects of night vs morning administration of zoledronic acid (ZA) on bone turnover. Forty-four breast cancer patients with bone metastases were randomised to receive intravenous ZA (4 mg) at 1100 or 2300 hours every 28 days for four times. Urinary concentration N-telopeptide of type-I collagen (NTX) and deoxypyridinolines, and serum C-telopeptide of type-I collagen (CTX), bone alkaline phosphatase (ALP), osteocalcin and Parathyroid hormone (PTH) was measured in the morning at baseline and after 4, 7, 14, 28, 56 and 84 days. Urinary ZA concentration was also measured. Zoledronic acid caused significant decreases of NTX and CTX (P<0.001), without any difference in percent changes between night and morning arms. Bone ALP and osteocalcin were also significantly affected by ZA (P=0.001), without any difference between arms. Parathyroid hormone significantly increased in both the arms; PTH increase was lower in the night arm (P=0.001). From the second administration onwards, urinary ZA level was significantly higher in the night arm (P<0.01). Administration of ZA at two opposite phases of the circadian cycle causes similar changes of bone-turnover marker levels, but has differential effects on the level of serum PTH.
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PMID:Changes of bone turnover markers and serum PTH after night or morning administration of zoledronic acid in breast cancer patients with bone metastases. 1850 77

Osteoporosis is a systemic disease characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in an increased risk of fracture. While the level of bone mass can be estimated by measuring bone mineral density (BMD) using dual X-ray absorptiometry (DXA), its measurement does not capture all the risk factors for fracture. Quantitative changes in skeletal turnover can be assessed easily and non-invasively by the measurement of serum and urinary biochemical markers; the most sensitive markers include serum osteocalcin, bone specific alkaline phosphatase, the N-terminal propeptide of type I collagen for bone formation, and the crosslinked C- (CTX) and N- (NTX) telopeptides of type I collagen for bone resorption. Advances in our knowledge of bone matrix biochemistry, most notably of post-translational modifications in type I collagen, are likely to lead to the development of new biochemical markers that reflect changes in the material property of bone, an important determinant of bone strength. Among those, the measurement of the urinary ratio of native (alpha) to isomerized (beta) CTX - an index of bone matrix maturation - has been shown to be predictive of fracture risk independently of BMD and bone turnover. In postmenopausal osteoporosis, levels of bone resorption markers above the upper limit of the premenopausal range are associated with an increased risk of hip, vertebral, and nonvertebral fracture, independent of BMD. Therefore, the combined use of BMD measurement and biochemical markers is helpful in risk assessment, especially in those women who are not identified as at risk by BMD measurement alone. Levels of bone markers decrease rapidly with antiresorptive therapies, and the levels reached after 3-6 months of therapy have been shown to be more strongly associated with fracture outcome than changes in BMD. Preliminary studies indicate that monitoring changes of bone formation markers could also be useful to monitor anabolic therapies, including intermittent parathyroid hormone administration and, possibly, to improve adherence to treatment. Thus, repeated measurements of bone markers during therapy may help improve the management of osteoporosis in patients.
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PMID:Biomarkers for osteoporosis management: utility in diagnosis, fracture risk prediction and therapy monitoring. 1851 Mar 79

The first weeks of lactation in dairy cows are characterised by elevated bone resorption. The connection between lactation and bone metabolism is still much discussed. In this work, changes in the concentration of plasma parathyroid hormone-related peptide (PTHrP) and markers of bone metabolism were studied in Holstein cows and heifers in the dry period and early lactation to determine the role of PTHrP in the relationship between the rate of bone remodelling and the onset of lactation in dairy cows. Blood samples were taken 14 days before calving ('D-14', n = 23) and then on day 10 ('D+10', n = 21) and day 30 after calving ('D+30', n = 23). Using enzyme immunoassay (EIA), the concentrations of PTHrP, parathyroid hormone (PTH), carboxyterminal cross-linked telopeptide of type I collagen (CTX) and oestradiol and the activity of bone specific alkaline phosphatase (BSALP) were determined. The results showed a statistically significant increase in plasma PTHrP (p < 0.005) and CTX (p < 0.0001) in cows on 'D+10' as compared to 'D-14' and CTX on 'D+30' as compared to 'D-14' (p < 0.0001). Significant negative correlations were found between the concentrations of PTHrP and oestradiol (r = -0.29, p < 0.05) and those of CTX and oestradiol (r = -0.54, p < 0.0001). In nonpregnant heifers (n = 6), the concentration of CTX and the activity of BSALP were significantly higher (p < 0.0001) than in dry cows. The observed increments of PTHrP and bone resorption after parturition reveal adaptations of bone metabolism to lactation in dairy cows.
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PMID:Plasma parathyroid hormone-related peptide and bone metabolism in periparturient dairy cows. 1866 51

Ageing is associated with a gradual bone loss and physical activity has been suggested as practical strategy for a non-pharmacological prevention of osteoporosis. However, until now, the specific mechanism by which physical activity affects bone tissue is not thoroughly understood. The aim of this study was to evaluate the effect of strenuous exercise on bone metabolism as a function of age and fitness level. Eighteen physically highly active elderly participants (mean age 71.7+/-7.3 years, HAcEl group), 18 moderately active elderly participants (mean age 71.9+/-8.6 years, ModEl group) and 9 young physically active participants (mean age 25.8+/-2.3 years, AcYo) participated in this study. Concentrations of plasma ionised calcium (iCa), serum parathyroid hormone (iPTH), 25-hydroxy-vitamin D [25(OH)D], and 1,25-dihydroxy-vitamin D3 [1,25(OH)(2)D3] as well as the bone biochemical markers type-I collagen C-telopeptide (CTX) for bone resorption and osteocalcin (OC) and bone alkaline phosphatase (B-ALP) for bone formation, were analyzed before and after a maximal incremental exercise test. In all groups, iCa decreased significantly (p<0.05 for ModEl and AcYo and p<0.001 for HAcEl) while iPTH increased significantly (p<0.01 for ModEl and HAcEl and p<0.001 for AcYo) after exercise. The levels of 1,25(OH)(2)D3, OC and CTX remained unchanged, while 25(OH)D decreased only in HAcEl group while B-ALP increased in ModEl group. In conclusion, strenuous exercise disturbed calcium homeostasis, mainly the iCa/iPTH equilibrium independently of gender, age or fitness level of the participants while no immediate effect on bone turnover was observed.
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PMID:Response of calciotropic hormones and bone turnover to brisk walking according to age and fitness level. 1876 64

The dose-response efficacy and safety with three doses of teriparatide and placebo was assessed, using once-daily subcutaneous injections for 24 weeks, in Japanese postmenopausal women with osteoporosis at high risk of fracture for reasons of preexisting fracture(s), advanced age, and/or low bone mineral density (BMD). In this multicenter, randomized, placebo-controlled study, 159 subjects were randomized and 154 subjects were included for analysis. Teriparatide (10-microg, 20-microg, and 40-microg doses) showed a statistically significant increase with increasing treatment dose as assessed by the percent change of lumbar spine BMD from baseline to endpoint using Williams' test when compared with placebo (P < 0.001). The mean (+/-SD) percent change in lumbar spine, femoral neck, and total hip BMD with the 20-microg dose from baseline to endpoint was 6.40% +/- 4.76%, 1.83% +/- 7.13%, and 1.91% +/- 3.60%, respectively. Rapid and sustained increases in bone formation markers [type I procollagen N-terminal propeptide (PINP), type I procollagen C-terminal propeptide (PICP), and bone-specific alkaline phosphatase (BAP)], followed by late increases in a bone resorption marker [type I collagen cross-linked C-telopeptide (CTX)], were observed for the teriparatide treatment groups (20-microg, 40-microg), suggesting a persistent, positive, balanced anabolic effect of teriparatide. Optimal adherence was achieved by this daily self-injection treatment. Regarding safety, most of the adverse events were mild to moderate in severity. No study drug-or study procedure-related serious adverse events were reported during the treatment period. These results observed in Japanese patients may support the observation that teriparatide stimulates bone formation in patients with osteoporosis at a high risk of fracture.
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PMID:Effect of teriparatide on bone mineral density and biochemical markers in Japanese women with postmenopausal osteoporosis: a 6-month dose-response study. 1897 63

Lithium salts are widely used in treating psychiatric patients. Lithium may be associated with hyperparathyroidism, a risk factor for osteoporosis. However, the data on the effect of lithium on bone mass are conflicting. We assessed bone mineral density with dual-energy X-ray absorptiometry at the hip and lumbar spine in 75 lithium treated outpatients and 75 normal subjects matched for age, sex and body mass index. Serum total calcium, intact parathyroid hormone (PTH), estradiol, osteocalcin, total alkaline phosphatase (ALP) and C-telopeptide (CTX) in addition to fasting urinary calcium excretion were also determined in both groups. The mean (+/-SD) bone density in lithium treated patients was 4.5% higher at the spine (P<0.05), 5.3% higher at the femoral neck (P<0.05) and 7.5% higher at the trochanter (P<0.05). In addition, lithium treated patients had lower serum total ALP (P<0.005), lower serum osteocalcin (P<0.005) and lower serum CTX (P<0.05) but the total calcium, PTH and urinary calcium excretion did not differ significantly between patients and controls. In conclusion, our results suggest that maintenance therapy with lithium carbonate may preserve or enhance bone mass. These data also suggest a lower bone turnover state in those receiving lithium.
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PMID:Lithium's effect on bone mineral density. 1899 57

The effects of ACE-011 on safety, pharmacokinetics, and bone biomarkers were evaluated in healthy, postmenopausal women. Our data indicate that ACE-011 results in a sustained increase in biomarkers of bone formation and reduction in markers of bone resorption. The activin type IIA receptor (ActRIIA) is the high-affinity receptor for activin. ACE-011 is a dimeric fusion protein consisting of the extracellular domain of the human ActRIIA linked to the Fc portion of human IgG1. ACE-011 binds to activin, preventing activin from binding endogenous receptors. A randomized, double-blind, placebo-controlled study was conducted to evaluate the safety and tolerability of ACE-011. Forty-eight healthy, postmenopausal women were randomized to receive either a single dose of ACE-011 or placebo and were followed for 4 mo. Dose levels ranged from 0.01 to 3.0 mg/kg intravenously and from 0.03 to 0.1 mg/kg subcutaneously. Safety and pharmacokinetic (PK) analyses and the biological activity of ACE-011, as assessed by markers of bone turnover, and follicle stimulating hormone (FSH) levels were measured. No serious adverse events (AEs) were reported. AEs were generally mild and transient. The PK of ACE-011 was linear over the dose range studied, with a mean half-life of 24-32 days. The absorption after subcutaneous dosing was essentially complete. ACE-011 caused a rapid and sustained dose-dependent increase in serum levels of bone-specific alkaline phosphatase (BSALP) and a dose-dependent decrease in C-terminal type 1 collagen telopeptide (CTX) and TRACP-5b levels. There was also a dose-dependent decrease in serum FSH levels consistent with inhibition of activin. ACE-011 is a novel agent with biological evidence of both an increase in bone formation and a decrease in bone resorption. ACE-011 may be an effective therapy in a variety of diseases involving bone loss.
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PMID:Single-dose, randomized, double-blind, placebo-controlled study of ACE-011 (ActRIIA-IgG1) in postmenopausal women. 1904 40

Poor vitamin D status is common in the elderly and is associated with bone loss and fractures. The aim was to assess worldwide vitamin D status in postmenopausal women with osteoporosis according to latitude and economic status, in relation to parathyroid function, bone turnover markers, and BMD. The study was performed in 7441 postmenopausal women from 29 countries participating in a clinical trial on bazedoxifene (selective estrogen receptor modulator), with BMD T-score at the femoral neck or lumbar spine <or= -2.5 or one to five mild or moderate vertebral fractures. Serum 25(OH)D, PTH, alkaline phosphatase (ALP), bone turnover markers osteocalcin (OC) and C-terminal cross-linked telopeptides of type I collagen (CTX), and BMD of the lumbar spine, total hip, femoral neck, and trochanter were measured. The mean serum 25(OH)D level was 61.2 +/- 22.4 nM. The prevalence of 25(OH)D <25, 25-50, 50-75, and >75 nM was 5.9%, 29.4%, 43.5%, and 21.2%, respectively, in winter and 3.0%, 22.2%, 47.2%, and 27.5% in summer. Worldwide, a negative correlation between 25(OH)D and latitude was observed. With increasing 25(OH)D categories of <25, 25-50, 50-75, and >75 nM, mean PTH, OC, and CTX were decreasing (p < 0.001), whereas BMD of all sites was increasing (p < 0.001). A threshold in the positive relationship between 25(OH)D and different BMD parameters was visible at a 25(OH)D level of 50 nM. Our study showed a high prevalence of low 25(OH)D in postmenopausal women with osteoporosis worldwide. Along with latitude, affluence seems to be an important factor for serum 25(OH)D level, especially in Europe, where it is strongly correlated with latitude.
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PMID:Vitamin D status, parathyroid function, bone turnover, and BMD in postmenopausal women with osteoporosis: global perspective. 1904 41

Glucocorticoid (GC)-induced osteoporosis (GIO) is the most important secondary cause of bone loss. Clinical evidence suggests a role for genistein (GEN) aglycone in the prevention of osteoporosis. We investigated whether GEN could prevent GIO as well as the development of osteonecrosis in the femoral head using an experimental rat model. A total of 28 female Sprague-Dawley rats were used in the study. GIO and osteonecrosis were induced by daily s.c. injections of 30 mg/kg of methylprednisolone (MP; n=7). Another group of animals (MP+GEN; n=7) concomitantly received MP (30 mg/kg per s.c.) and GEN aglycone (5 mg/kg per i.p.) for 60 days. Control animals were administered daily with vehicle (VEH) or GEN (5 mg/kg per i.p.) only. At the beginning and end of the treatment, animals were examined for bone mineral density (BMD) and bone mineral content (BMC). After killing, serum was collected to determine bone-alkaline phosphatase (b-ALP), carboxy-terminal collagen crosslink (CTX) and osteoprotegerin (OPG) levels. Femurs were removed and tested for breaking strength and bone histology analyzed for structural quality of the femoral neck. GEN aglycone prevented bone loss as measured by BMD and BMC. Moreover, GEN significantly increased the bone formation markers b-ALP and OPG, reduced the bone resorption marker CTX and statistically maintained comparable strength versus the VEH only group. Finally, histological scoring revealed a protective effect of GEN on bone structure statistically comparable with the VEH control animals. Results suggest that the GEN aglycone might be a preventive treatment for GIO and complications of osteonecrosis with long-term GC treatment.
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PMID:Protective effect of genistein aglycone on the development of osteonecrosis of the femoral head and secondary osteoporosis induced by methylprednisolone in rats. 1933 50


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