For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
8
views
20
references
 Top references
cited by
5
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      513
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Disease Systems Analysis of Bone Mineral Density and Bone Turnover Markers in Response to Alendronate, Placebo, and Washout in Postmenopausal Women

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          A previously established mechanism‐based disease systems model for osteoporosis that is based on a mathematically reduced version of a model describing the interactions between osteoclast (bone removing) and osteoblast (bone forming) cells in bone remodeling has been applied to clinical data from women ( n = 1,379) receiving different doses and treatment regimens of alendronate, placebo, and washout. The changes in the biomarkers, plasma bone‐specific alkaline phosphatase activity (BSAP), urinary N‐telopeptide (NTX), lumbar spine bone mineral density (BMD), and total hip BMD, were linked to the underlying mechanistic core of the model. The final model gave an accurate description of all four biomarkers for the different treatments. Simulations were used to visualize the dynamics of the underlying network and the natural disease progression upon alendronate treatment and discontinuation. These results complement the previous applications of this mechanism‐based disease systems model to data from various treatments for osteoporosis.

          Related collections

          Most cited references20

          • Record: found
          • Abstract: found
          • Article: not found

          Piraña and PCluster: a modeling environment and cluster infrastructure for NONMEM.

          Ron J. Keizer, Michel van Benten, Jos H. Beijnen … (2011)
          Pharmacokinetic-pharmacodynamic modeling using non-linear mixed effects modeling (NONMEM) is a powerful yet challenging technique, as the software is generally accessed from the command line. A graphical user interface, Piraña, was developed that offers a complete modeling environment for NONMEM, enabling both novice and advanced users to increase efficiency of their workflow. Piraña provides features for the management and creation of model files, the overview of modeling results, creation of run reports and handling of datasets and output tables, and the running of custom R scripts on model output. Through the secure shell (SSH) protocol, Piraña can also be used to connect to Linux clusters (SGE, MOSIX) for distribution of workload. Modeling with NONMEM is computationally burdensome, which may be alleviated by distributing runs to computer clusters. A solution to this problem is offered here, called PCluster. This platform is easy to set up, runs in standard network environments, and can be extended with additional nodes if needed. The cluster supports the modeling toolkit Perl speaks NONMEM (PsN), and can include dedicated or non-dedicated PCs. A daemon script, written in Perl, was designed to run in the background on each node in the cluster, and to manage job distribution. The PCluster can be accessed from Piraña, and both software products have extensively been tested on a large academic network. The software is available under an open-source license. 2011 Elsevier Ireland Ltd. All rights reserved.
          Article 0 comments Cited 111 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro.

            J M Halasy, David Russell, P Masarachia … (1999)
            Nitrogen-containing bisphosphonates were shown to cause macrophage apoptosis by inhibiting enzymes in the biosynthetic pathway leading from mevalonate to cholesterol. This study suggests that, in osteoclasts, geranylgeranyl diphosphate, the substrate for prenylation of most GTP binding proteins, is likely to be the crucial intermediate affected by these bisphosphonates. We report that murine osteoclast formation in culture is inhibited by both lovastatin, an inhibitor of hydroxymethylglutaryl CoA reductase, and alendronate. Lovastatin effects are blocked fully by mevalonate and less effectively by geranylgeraniol whereas alendronate effects are blocked partially by mevalonate and more effectively by geranylgeraniol. Alendronate inhibition of bone resorption in mouse calvaria also is blocked by mevalonate whereas clodronate inhibition is not. Furthermore, rabbit osteoclast formation and activity also are inhibited by lovastatin and alendronate. The lovastatin effects are prevented by mevalonate or geranylgeraniol, and alendronate effects are prevented by geranylgeraniol. Farnesol and squalene are without effect. Signaling studies show that lovastatin and alendronate activate in purified osteoclasts a 34-kDa kinase. Lovastatin-mediated activation is blocked by mevalonate and geranylgeraniol whereas alendronate activation is blocked by geranylgeraniol. Together, these findings support the hypothesis that alendronate, acting directly on osteoclasts, inhibits a rate-limiting step in the cholesterol biosynthesis pathway, essential for osteoclast function. This inhibition is prevented by exogenous geranylgeraniol, probably required for prenylation of GTP binding proteins that control cytoskeletal reorganization, vesicular fusion, and apoptosis, processes involved in osteoclast activation and survival.
            Article 0 comments Cited 79 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Modeling the interactions between osteoblast and osteoclast activities in bone remodeling.

              Vincent Lemaire, Frank Tobin, Larry Greller … (2004)
              We propose a mathematical model explaining the interactions between osteoblasts and osteoclasts, two cell types specialized in the maintenance of the bone integrity. Bone is a dynamic, living tissue whose structure and shape continuously evolves during life. It has the ability to change architecture by removal of old bone and replacement with newly formed bone in a localized process called remodeling. The model described here is based on the idea that the relative proportions of immature and mature osteoblasts control the degree of osteoclastic activity. In addition, osteoclasts control osteoblasts differentially depending on their stage of differentiation. Despite the tremendous complexity of the bone regulatory system and its fragmentary understanding, we obtain surprisingly good correlations between the model simulations and the experimental observations extracted from the literature. The model results corroborate all behaviors of the bone remodeling system that we have simulated, including the tight coupling between osteoblasts and osteoclasts, the catabolic effect induced by continuous administration of PTH, the catabolic action of RANKL, as well as its reversal by soluble antagonist OPG. The model is also able to simulate metabolic bone diseases such as estrogen deficiency, vitamin D deficiency, senescence and glucocorticoid excess. Conversely, possible routes for therapeutic interventions are tested and evaluated. Our model confirms that anti-resorptive therapies are unable to partially restore bone loss, whereas bone formation therapies yield better results. The model enables us to determine and evaluate potential therapies based on their efficacy. In particular, the model predicts that combinations of anti-resorptive and anabolic therapies provide significant benefits compared with monotherapy, especially for certain type of skeletal disease. Finally, the model clearly indicates that increasing the size of the pool of preosteoblasts is an essential ingredient for the therapeutic manipulation of bone formation. This model was conceived as the first step in a bone turnover modeling platform. These initial modeling results are extremely encouraging and lead us to proceed with additional explorations into bone turnover and skeletal remodeling.
              Article 0 comments Cited 74 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                J Berkhout: jberkh@gmail.com
                Journal
                Journal ID (nlm-ta): CPT Pharmacometrics Syst Pharmacol
                Journal ID (iso-abbrev): CPT Pharmacometrics Syst Pharmacol
                Journal ID (doi): 10.1002/(ISSN)2163-8306
                Journal ID (publisher-id): PSP4
                Title: CPT: Pharmacometrics & Systems Pharmacology
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2163-8306
                Publication date (Electronic): 21 November 2016
                Publication date (Print): December 2016
                Volume: 5
                Issue: 12 ( doiID: 10.1002/psp4.v5.12 )
                Pages: 656-664
                Affiliations
                [ 1 ] Department of Medical InformaticsErasmus Medical Centre RotterdamThe Netherlands
                [ 2 ]Leiden Academic Centre for Drug Research, Division of Pharmacology LeidenThe Netherlands
                [ 3 ]Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P) LeidenThe Netherlands
                [ 4 ]Merck Sharp & Dohme Corp. Kenilworth New JerseyUSA
                Author notes
                [*] [* ]Correspondence: J Berkhout ( jberkh@ 123456gmail.com )
                Article
                Publisher ID: PSP412135
                DOI: 10.1002/psp4.12135
                PMC ID: 5193000
                PubMed ID: 27869358
                SO-VID: d05c8aff-16bf-4077-a7ab-646ae2e92dc7
                Copyright © © 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics
                License:

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 01 April 2016
                Date accepted : 08 September 2016
                Page count
                Figures: 5, Tables: 2, Pages: 9, Words: 5721
                Categories
                Subject: Original Article
                Subject: Original Articles
                Custom metadata
                source-schema-version-number 2.0
                component-id psp412135
                cover-date December 2016
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.0.0 mode:remove_FC converted:28.12.2016

                Data availability:

                Comments

                Comment on this article

                scite_

                Similar content513

                See all similar

                Cited by5

                See all cited by

                Most referenced authors198

                See all reference authors