Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The objective of this study was to assess the relationship between the bone strontium content and bone histomorphometric parameters in bone biopsies from patients with chronic renal failure undergoing hemodialysis. The study was carried out in 74 illiac crest bone biopsies from patients with renal osteodystrophy from different worldwide regions (Argentina, Portugal and Spain). They were underwent to histological and histomorphometric evaluation. The bone strontium/calcium ratio was measured by quadrupole inductively coupled plasma-mass spectrometry. The samples were classified into groups according to histological criteria: hyperparathyroidism (HP), mixed (MX), osteomalacia (OM) and adynamic bone disease (ABD). Serum PTH and alkaline phosphatase before biopsy were available in most of the patients. No correlation was found between the different histomorphometric parameters and the Sr/Ca ratio. The one way ANOVA test showed statistical differences in the Sr/Ca ratio of the different histological forms (HP: 0.58 +/- 0.39; MX: 1.16 +/- 0.74; OM: 1.10 +/- 0.46; ABD: 0.91 +/- 0.40 microgram Sr/mg Ca; p < 0.003). The post-Hoc analysis showed differences between HP and MX. The biopsies having greater or equal values than 1.4 micrograms Sr/mg Ca showed higher levels of bone formation histomorphometric parameters and serum alkaline phosphatase (395 +/- 519 vs 1,022 +/- 989 UI/L, p < 0.05). Although it has been found that the biopsies with higher bone strontium had higher levels of osteoid tissue (characteristic of osteomalacia), the hypothesis of strontium-induced osteomalacia could not be demonstrated.
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PMID:[Effect of strontium on bone metabolism in hemodialysis patients]. 1277 55

There is growing evidence that strontium ranelate (SR; S12911-2, PROTELOS; Institut de Recherches Internationales Servier, Courbevoie, France), a compound containing 2 atoms of stable strontium (Sr), influences bone cells and bone metabolism in vitro and in vivo. We previously reported that SR increases bone mass in rats and mice by stimulating bone formation and inhibiting bone resorption. We also showed that short-term treatment with SR enhances osteoblastic cell recruitment and function in short-term rat calvaria cultures. Because Sr incorporates into the bone matrix, it was of interest to determine whether SR may affect matrix mineralization in long-term culture. To this goal, osteogenic mouse calvaria-derived MC3T3-E1 osteoblastic cells were cultured for up to 14 days in the presence of ascorbic acid and phosphate to induce matrix formation and mineralization. Matrix formation was determined by incorporation of tritiated proline during collagen synthesis. Matrix mineralization was quantified by measuring the number and surface of mineralized nodules using a digital image analyzer. In this model, 1,25(OH)2 vitamin D (1 nmol/L) used as internal control, increased alkaline phosphatase (ALP) activity, an early osteoblast marker, on days 4, 10, and 14 of culture. Treatment with SR (1 mmol/L Sr(2+)) increased ALP activity at days 4 and 14 of culture. SR also increased collagen synthesis at days 4 and 10 of culture. In contrast, 1,25(OH)2 vitamin D (1 nmol/L) inhibited collagen synthesis at 4 to 14 days of culture. Long-term treatment with SR (0.1 to 1 mmol/L Sr(2+)) dose dependently increased Sr concentration into the calcified nodules, but did not alter matrix mineralization in long-term culture, as shown by the ratio of the surface of mineralized nodules to the number of mineralized nodules on day 14 of culture. These results show that long-term treatment with SR increases collagenous matrix formation by MC3T3-E1 osteoblasts without inducing deleterious effect on matrix mineralization.
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PMID:Normal matrix mineralization induced by strontium ranelate in MC3T3-E1 osteogenic cells. 1504 4

Strontium ranelate has been shown to decrease the risk of fractures in postmenopausal women. Its efficacy in clinical studies results from its unique mode of action, on both bone resorption and bone formation. Pharmacological studies in animals have shown that strontium ranelate decreases bone resorption and increases bone formation, resulting in increased bone mass. In ovariectomized rats, strontium ranelate prevented the reduction in bone mineral content and the decrease in trabecular bone volume induced by estrogen deficiency. In this model, strontium ranelate decreased bone resorption, whereas bone formation was maintained at a high level as documented by plasma biochemical markers and histomorphometric indices of bone formation. In the model of osteopenia induced by hind-limb immobilization in rats, strontium ranelate reduced histomorphometric parameters of bone resorption and partially prevented long-bone loss, as assessed by bone mineral content, bone volume, and biochemical indices of bone resorption. In intact mice, strontium ranelate increased bone formation and vertebral bone mass. In intact growing rats, strontium ranelate increased the bone trabecular volume without alteration of mineralization. The unique mode of action of strontium ranelate on bone formation and resorption was supported by in vitro studies. In rat calvaria culture systems and rat osteoblastic cell cultures, strontium ranelate enhanced preosteoblastic cell replication and increased collagen synthesis by osteoblasts. Moreover, strontium ranelate decreased bone resorption in organ cultures and decreased the resorbing activity of isolated mouse osteoclasts. The assessment of bone markers in a clinical trial [Spinal Osteoporosis Therapeutic Intervention (SOTI)] supports the mode of action of strontium ranelate: bone alkaline phosphatase levels increased and C-telopeptide of type I collagen levels decreased in treated patients compared with the placebo group at all time points. Thus, pharmacological and clinical studies suggest that strontium ranelate optimizes bone resorption and bone formation, resulting in increased bone mass, which may be of great value in the treatment of osteoporosis.
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PMID:Strontium ranelate: a novel mode of action optimizing bone formation and resorption. 1557 59

In a previous experimental study using a chronic renal failure rat model, a dose-related multiphasic effect of strontium (Sr) on bone formation was found that could be reproduced in an in vitro set-up using primary rat osteoblasts. The results from the latter study allowed us to distinguish between a reduced nodule formation in the presence of an intact mineralization at low Sr-doses (1 microg/ml) and an interference of the element with the hydroxyapatite (HA) formation at high doses (20-100 microg/ml). To further investigate the latter effect of Sr on physicochemical bone mineral properties, an in vitro study was set up in which the UMR-106 rat osteosarcoma cell line was exposed to Sr, added to the cell culture medium in a concentration range varying between 0-100 microg/ml. Temporal growth and functionality of the culture was investigated by measurement of the alkaline phosphatase activity and calcium (Ca) concentration in the culture medium (used as an index of Ca-incorporation, i.e., HA formation) at various time points. At the end of the culture period (14 days post-confluence), samples of the mineralized cultures were taken for further analysis using X-ray diffraction (XRD) and Fourier Transform Infra-Red Spectroscopy (FTIR). Synthetic HA doped with various Sr concentrations (based on the cell culture and previous experimental studies and yielding Sr/(Sr + Ca) ratios ranging from 0-60%), was prepared and examined for crystal growth and solubility. Crystal size was assessed using scanning electron microscopy (SEM). Ca incorporation indicated a reduced mineralization in the 20 and 100 microg/ml Sr groups vs. controls. Sr-doped synthetic HA showed a significant dose-dependent reduction in crystal growth, as assessed by SEM, and an increase in solubility, apparent from 12.7% Sr/(Sr + Ca) on. Moreover, in both mineralized cultures and synthetic HA, XRD and FTIR analysis showed a reduced crystallinity and altered crystal lattice at similar concentrations. These new data support our previous in vivo and in vitro findings and point to a potential physicochemical interference of Sr with HA formation and crystal properties in vivo.
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PMID:Effects of strontium on the physicochemical characteristics of hydroxyapatite. 1559 97

Osteoporosis associated with estrogen deficiency results from an imbalance between bone resorption and formation, causing deterioration of bone architecture and decreased bone mass. Anti-osteoporotic therapies that have been developed so far include either anticatabolic or anabolic drugs. Strontium ranelate is a newly developed drug that induces opposite effects on bone resorption and formation. This dual original mode of action was demonstrated in experimental studies on bone cells and pharmacological studies in animals. In vitro, strontium ranelate was shown to decrease bone resorption. This effect resulted from a decreased differentiation and resorbing activity of osteoclasts and increased osteoclast apoptosis. In contrast, strontium ranelate was shown to enhance preosteoblastic cell replication and collagen synthesis in culture without affecting bone mineralization. In vivo, strontium ranelate promoted bone formation and reduced bone resorption in intact mice, an effect which resulted in increased vertebral bone mass. Additionally, strontium ranelate was found to reduce resorption and long bone loss induced by hind limb immobilization in rats. Finally, strontium ranelate administration decreased bone resorption and maintained bone formation in adult ovariectomized rats, which resulted in prevention of bone loss. In clinical trials (Spinal Osteoporosis Therapeutic Intervention [SOTI]), bone alkaline phosphatase levels increased, whereas C cross-linking telopeptide of type I collagen (CTX) levels decreased in patients treated with strontium ranelate compared with placebo at all time points. These pharmacological and clinical studies suggest that strontium ranelate acts by increasing bone formation and decreasing bone resorption and that these effects result in improved bone mass in vivo.
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PMID:Strontium ranelate: a physiological approach for optimizing bone formation and resorption. 1643 91

The increased bone remodeling in women after menopause induces an imbalance between bone resorption and formation, leading to decreased bone mass, altered bone microarchitecture, and increased fracture risk. Current antiosteoporotic drugs decrease bone remodeling or increase bone formation. Strontium ranelate (Protelos) is a newly developed antiosteoporotic drug that acts by reducing bone resorption and promoting bone formation, thereby inducing a positive bone balance. In rat and mouse culture models, strontium ranelate enhances preosteoblastic cell replication and bone formation markers. In contrast, it decreases rodent osteoclastic cell resorbing activity and human osteoclast differentiation, and increases rabbit osteoclast apoptosis. In vivo, strontium ranelate increases bone formation and reduces bone resorption in mice, resulting in increased vertebral bone mass. In rats, strontium ranelate increases bone mass and improves microarchitecture and bone geometry, resulting in increased bone resistance. In ovariectomized rats, strontium ranelate decreases bone resorption but maintains high bone formation, resulting in improved bone microarchitecture and increased bone mass and strength. In clinical trials, serum alkaline phosphatase levels increased whereas serum CTX levels simultaneously decreased in patients treated with Protelos versus placebo at all time-points. In these trials, histomorphometric analysis of bone biopsies showed that the osteoblast surface and mineral apposition rate increased whereas bone resorption parameters tended to decrease in treated patients compared to the placebo group. These preclinical and clinical data indicate that strontium ranelate acts by increasing bone formation and decreasing bone resorption, thus rebalancing bone turnover in favour of bone formation, an effect that results in increased bone mass and strength.
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PMID:Strontium ranelate: a dual mode of action rebalancing bone turnover in favour of bone formation. 1673 40

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 the drug enhanced preosteoblastic cell replication. In the isolated rat osteoclast, a preincubation of bone slices with strontium ranelate induced a dose-dependent inhibition of the bone resorbing activity of treated rat osteoclast. Strontium ranelate dose-dependently inhibited preosteoclast differentiation. In a phase II dose ranging trial Strontium ranelate (500 mg, 1000 mg, 2000 mg/day) or placebo were given to 353 postmenopausal women with prevalent vertebral osteoporosis. At the conclusion of this 2-year study, the annual increase in lumbar BMD of the group receiving 2000 mg of strontium ranelate was + 7.3%, a significant increase in bone alkaline phosphatase, over a 6-month period and a significant decrease in N-telopeptide crosslinks throughout the 2-year period were seen. During the second year of treatment, the dose of 2000 mg was associated with a 44% reduction in the number of patients experiencing a new vertebral deformity. The primary analysis of the SOTI study, evaluating the effect of strontium ranelate 2000 mg on vertebral fracture rates, revealed a 41% reduction in the relative risk of patient experiencing a first new vertebral fracture with strontium ranelate throughout the 3-year study. The TROPOS study showed a significant reduction in the risk of experiencing a first non-vertebral fracture by 16% in the group treated with strontium ranelate throughout the 3-year study. A reduction in the risk of experiencing a hip fracture by 36% was also demonstrated in the patients at high risk of hip fracture (age > or =74 years and Femoral Neck T score < or = -2.4 according to NHANES normative value). All these results suggest that strontium ranelate is a new, effective and safe treatment of vertebral and non-vertebral osteoporosis, with a unique mode of action.
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PMID:Comprehensive therapy in osteoporosis using a single drug: from ADFR to strontium ranelate. 1678 5

Strontium is used in the treatment of osteoporosis as a ranelate compound, and in the treatment of painful scattered bone metastases as isotope. At very high doses and in certain conditions, it can lead to osteomalacia characterized by impairment of bone mineralization. The osteomalacia symptoms resemble those of hypophosphatasia, a rare inherited disorder associated with mutations in the gene encoding for tissue-nonspecific alkaline phosphatase (TNAP). Human alkaline phosphatases have four metal binding sites--two for zinc, one for magnesium, and one for calcium ion--that can be substituted by strontium. Here we present the crystal structure of strontium-substituted human placental alkaline phosphatase (PLAP), a related isozyme of TNAP, in which such replacement can have important physiological implications. The structure shows that strontium substitutes the calcium ion with concomitant modification of the metal coordination. The use of the flexible and polarizable force-field TCPEp (topological and classical polarization effects for proteins) predicts that calcium or strontium has similar interaction energies at the calcium-binding site of PLAP. Since calcium helps stabilize a large area that includes loops 210-228 and 250-297, its substitution by strontium could affect the stability of this region. Energy calculations suggest that only at high doses of strontium, comparable to those found for calcium, can strontium substitute for calcium. Since osteomalacia is observed after ingestion of high doses of strontium, alkaline phosphatase is likely to be one of the targets of strontium, and thus this enzyme might be involved in this disease.
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PMID:Structural studies of human alkaline phosphatase in complex with strontium: implication for its secondary effect in bones. 1681 19

The objective of this study was to investigate the in vitro bioactivity of strontium-containing hydroxyapatite (Sr-HA), and its effect on cellular attachment, proliferation, and differentiation. The effect of Sr-HA has been compared with that of hydroxyapatite (HA), which is widely used in orthopedics and dentistry. Sr-HA ceramic containing 10 mol % was prepared. The bioactivity of Sr-HA was evaluated in vitro by immersion in simulated body fluid (SBF). After immersion in SBF, Sr-HA exhibited greater ability to induce apatite precipitation on its surface than did HA. The possible effects on cell behavior of Sr-HA were examined by culturing osteoprecursor cells (OPC1) on materials surfaces. Cell shape and cell-material interactions were analyzed by scanning electron microscope (SEM) and the MTT assay was used to determine cell proliferation on samples. When compared with HA, Sr-HA promoted better OPC1 cell attachment and proliferation, and showed no deleterious effects on extracellular matrix formation and mineralization. Confocal scanning microscopy was used to assess the expression of specific osteoblast proteins: alkaline phosphatase (ALP) and osteopontin (OPN). The results obtained indicate that the presence of Sr stimulates OPC1 cell differentiation, and enhances ALP and OPN expression.
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PMID:Osteoprecursor cell response to strontium-containing hydroxyapatite ceramics. 1688 20


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