Editorial
Statins and osteoporosis: A latent promise
Estatinas y osteoporosis: una promesa latente
Elda Leonor Pacheco-Pantoja
, Jose Alvarez-Nemegyei
Corresponding author
Escuela de Medicina, Universidad Anahuac Mayab, Mérida, Mexico
Read
5891
Timeswas read the article
2017
Total PDF
3874
Total HTML
Share statistics
array:23 [ "pii" => "S2173574314000938" "issn" => "21735743" "doi" => "10.1016/j.reumae.2014.04.002" "estado" => "S300" "fechaPublicacion" => "2014-07-01" "aid" => "682" "copyright" => "Elsevier España, S.L.. All rights reserved" "copyrightAnyo" => "2014" "documento" => "article" "crossmark" => 0 "subdocumento" => "sco" "cita" => "Reumatol Clin. 2014;10:201-3" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 2417 "formatos" => array:3 [ "EPUB" => 58 "HTML" => 1916 "PDF" => 443 ] ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S1699258X14001016" "issn" => "1699258X" "doi" => "10.1016/j.reuma.2014.04.005" "estado" => "S300" "fechaPublicacion" => "2014-07-01" "aid" => "682" "copyright" => "Elsevier España, S.L." "documento" => "article" "crossmark" => 0 "subdocumento" => "sco" "cita" => "Reumatol Clin. 2014;10:201-3" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 6711 "formatos" => array:3 [ "EPUB" => 181 "HTML" => 4918 "PDF" => 1612 ] ] "es" => array:10 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "Estatinas y osteoporosis: una promesa latente" "tienePdf" => "es" "tieneTextoCompleto" => "es" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "201" "paginaFinal" => "203" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Statins and osteoporosis: A latent promise" ] ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Elda Leonor Pacheco-Pantoja, Jose Alvarez-Nemegyei" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Elda Leonor" "apellidos" => "Pacheco-Pantoja" ] 1 => array:2 [ "nombre" => "Jose" "apellidos" => "Alvarez-Nemegyei" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2173574314000938" "doi" => "10.1016/j.reumae.2014.04.002" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574314000938?idApp=UINPBA00004M" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1699258X14001016?idApp=UINPBA00004M" "url" => "/1699258X/0000001000000004/v1_201406210040/S1699258X14001016/v1_201406210040/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S217357431400104X" "issn" => "21735743" "doi" => "10.1016/j.reumae.2013.12.025" "estado" => "S300" "fechaPublicacion" => "2014-07-01" "aid" => "638" "copyright" => "Elsevier España, S.L." "documento" => "article" "crossmark" => 0 "subdocumento" => "fla" "cita" => "Reumatol Clin. 2014;10:204-9" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 2535 "formatos" => array:3 [ "EPUB" => 50 "HTML" => 1750 "PDF" => 735 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original article</span>" "titulo" => "ASDAS high disease activity versus BASDAI elevation in patients with ankylosing spondylitis as selection criterion for anti-TNF therapy" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "204" "paginaFinal" => "209" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Actividad elevada ASDAS versus elevación de BASDAI en pacientes con espondilitis anquilosante como criterio de selección para el tratamiento con anti TNF-alfa" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2312 "Ancho" => 3095 "Tamanyo" => 902481 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Matrix representation of characteristics of patients selected with each criterion. Net numeric increase (green) or decrease (red) within each of the various subpopulations when the measure of disease activity used to select patients changes from elevated Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) to (A) Ankylosing Spondylitis Disease Activity Score (ASDAS) very high disease activity and (B) ASDAS high disease activity. Size of each of the 72 subpopulations, relative to the total population selected with the following disease activity measure: (C) very high ASDAS, (D) elevated BASDAI, and (E) high ASDAS. BASFI, Bath Ankylosing Spondylitis Functionality Index; CRP, C-reactive protein.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Nathan Vastesaeger, Bert Vander Cruyssen, Juan Mulero, Jordi Gratacós Masmitjá, Pedro Zarco, Raquel Almodovar, Pilar Font, Xavier Juanola, Eduardo Collantes-Estevez" "autores" => array:10 [ 0 => array:2 [ "nombre" => "Nathan" "apellidos" => "Vastesaeger" ] 1 => array:2 [ "nombre" => "Bert Vander" "apellidos" => "Cruyssen" ] 2 => array:2 [ "nombre" => "Juan" "apellidos" => "Mulero" ] 3 => array:2 [ "nombre" => "Jordi" "apellidos" => "Gratacós Masmitjá" ] 4 => array:2 [ "nombre" => "Pedro" "apellidos" => "Zarco" ] 5 => array:2 [ "nombre" => "Raquel" "apellidos" => "Almodovar" ] 6 => array:2 [ "nombre" => "Pilar" "apellidos" => "Font" ] 7 => array:2 [ "nombre" => "Xavier" "apellidos" => "Juanola" ] 8 => array:2 [ "nombre" => "Eduardo" "apellidos" => "Collantes-Estevez" ] 9 => array:1 [ "colaborador" => "on behalf of the REGISPONSER Working Group" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S1699258X14000035" "doi" => "10.1016/j.reuma.2013.12.006" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1699258X14000035?idApp=UINPBA00004M" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S217357431400104X?idApp=UINPBA00004M" "url" => "/21735743/0000001000000004/v1_201406280041/S217357431400104X/v1_201406280041/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial</span>" "titulo" => "Statins and osteoporosis: A latent promise" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "201" "paginaFinal" => "203" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Elda Leonor Pacheco-Pantoja, Jose Alvarez-Nemegyei" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Elda Leonor" "apellidos" => "Pacheco-Pantoja" "email" => array:2 [ 0 => "elda.pacheco@anahuac.mx" 1 => "pacheco.elda@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Jose" "apellidos" => "Alvarez-Nemegyei" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Escuela de Medicina, Universidad Anahuac Mayab, Mérida, Mexico" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Estatinas y osteoporosis: una promesa latente" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The clinical use of statins as therapeutic tools for osteoporosis has not yet reached the status of solid scientific dogma, even though it has been almost 15 years since the emergence of the first experimental evidence on the effect of this class of drugs on bone metabolism, specifically stimulating the formation of “new bone”. Statins are a group of competitive inhibitors consisting of the hydroxy-methyl-glutaryl-CoA (HMG-CoA) reductase and therefore have been widely used for the treatment of hypercholesterolemia.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The first experimental evidence in an animal model of the osteomodulador effect of statins was reported by Mundy et al.,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> who demonstrated that treatment with lovastatin, simvastatin, fluvastatin and mevastatin resulted in a significant increase (up to 2–3 times compared with controls) in the rates and bone formation markers, and that the effect of statins were comparable to that induced by treatment with bone morphogenetic protein-2 (BMP-2) and fibroblast growth factor, which are known stimulants of bone metabolism.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Other studies conducted in animal models, replicated the effects of statins as stimulating bone formation. However, the application of this knowledge to the treatment of metabolic bone diseases in humans has not been able to find solid support, as studies in humans have shown conflicting results.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The potential positive effect of statins on bone formation can be explained from three mechanisms: (a) the promotion of osteogenesis (b) suppression of apoptosis of osteoblasts and (c) inhibition of osteoclastogenesis.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The promotion of osteogenesis appears to be linked to mechanisms of prenylation as a posttranslational modification and necessary for certain key proteins in some signaling cascades. The HMG-CoA reductase enzyme catalyzes the synthesis of mevalonate, which is a limiting step for the formation reactions of farnesyl pyrophosphate and geranyl isoprenoids, which are the initial actions for the synthesis of cholesterol. The major effect of the statins is a decrease of the catalytic activity of HMG-CoA reductase, for the transformation of HMG-CoA to mevalonate, and finally the formation of farnesyl and geranyl pyrophosphate. These compounds are essential for small protein prenylation of guanosine triphosphate-binding proteins (G proteins monomeric),<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> required for activation and attachment to cell membranes, thereby terminating a series of signal transduction events. An example of these monomeric proteins is prenylated Rho G, which has shown to have an anti-osteogenic role. There is evidence that Rho and its target protein, Rho kinase, have a negative effect on bone formation<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and its inhibition promotes osteoblast differentiation.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Additionally, it has been shown that pitavastatin increases bone formation by inhibiting the prenylation and, therefore, the action of Rho and Rho kinase in addition to increasing the expression of BMP-2 mRNA and osteocalcin.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Some studies demonstrated that lovastatin at high serum concentrations (10–50<span class="elsevierStyleHsp" style=""></span>μM) inhibits the prenylation of Ras, Rho and Rap. Although the effect of these proteins is not observed with the therapeutic concentrations achieved using lipid-lowering doses (0.05–0.5<span class="elsevierStyleHsp" style=""></span>μM)<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> there is evidence to suggest that these concentrations would have some positive effect on a downstream signaling cascade composed of Akt and ERK molecules that are involved in the stimulation of osteogenesis.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">As for the second proposed mechanism, suppression of osteoblast apoptosis mediated by statins, a certain degree of apoptotic inhibition modulated by pitavastatin, mevastatin and simvastatin has been described, which is explained by the increased expression of the Smad3 protein (“mothers against decapentaplegic homolog 3”).<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> The Smad3 proteins are signal transducers and transcriptional modulators activated by transforming growth factor beta, which has a critical role in bone formation.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Additionally, inhibition of osteoblast apoptosis mediated by simvastatin in the cultured murine osteoblastic cell line MC3T3-E1 in a dose dependent manner has been demonstrated.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Finally, suppression of osteoclastogenesis promoted by statins appears to have a connection with the signaling pathway of osteoprotegerin (OPG), which is a ligand of receptor activator of nuclear factor κ B (RANK-L) and the activating nuclear factor receptor κ B (RANK). An in vitro study demonstrated that simvastatin and mevastatin increased the expression of OPG mRNA and caused reduced corresponding transcript expression of RANKL in primary cell cultures from explants of mouse bone.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In addition to this, it has been shown that inhibition of osteoclast function by statins could be explained by the effect exhibited by simvastatin on induction of the expression of estrogen receptor alpha in bone tissue of ovariectomized rats and their effect on the restoration of bone loss,<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> because this receptor has an important role in inhibiting osteoclastogenesis. Another plausible explanation for the inhibition of osteoclastogenesis is mediated by statins, in terms of interference with cytoskeletal osteoclast formation due to poor protein prenylation required for cell function.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The mismatch on the osteomodulador results of statins in humans can be explained by the extreme heterogeneity and methodological deficiencies in the design, and outcome measures of studies and the type of identifiable clinical reports devoted to topic analysis. Most studies have been cross-sectional and/or observational, or have relied on post hoc analysis of the data. Studies motivated by the publication of Mundy et al.,<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> have mostly studied patients with hypercholesterolemic in whom the outcome measure was bone mineral density (BMD),<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15–19</span></a> biochemical markers of bone remodeling, such as alkaline phosphatase, the amino-terminal propeptide of collagen type 1, the carboxy-terminal telopeptide of collagen<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20–24</span></a>; or combinations of BMD and biochemical indicators.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25–27</span></a> The few clinical studies using the reduced risk of fractures as an outcome measure show conflicting results, ranging from no effect to<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28–31</span></a> significant reduction in fracture risk.<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32–34</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Besides methodological issues, there are specific aspects that could explain, additionally, the discrepancy in the results on the osteomodulator clinical effect of statins in humans.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Statin doses used in clinical practice for the control of hypercholesterolemia exhibit no effect on the stimulation of bone formation, and that the doses used and the concentration ratios were much higher in the experimental models, studies reporting beneficial effects on bone formation compared to those used in human clinical studies.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,35,36</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Additionally, the type of statin used is a confounding factor to consider as the level of lipophilicity, polarity and bone avidity of the various compounds of class can result in a differential effect osteomodulador. The lipophilic statins appear more effective for bone formation than those of a hydrophilic nature, because apparently the first stimulate transcription of BMP-2, while the latter have not exhibited this action.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Another confounding factor in this respect lie in the hepatospecificity of statins. Taking into account the first step effect, the distribution of statins to the bone microenvironment could be much lower than expected. This explains the need of larger doses and concentrations for bone modulation compared with those required for the treatment of hypercholesterolemia, as only 5% of the ingested drug reaches the systemic circulation after the<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> hypolipidemic action in the liver.</p><p id="par0060" class="elsevierStylePara elsevierViewall">In conclusion, there is evidence from a number of from basic science and clinical research studies indicating that statins may be effective treatments for osteoporosis. However, this question needs to be answered by studies with appropriate experimental designs, sample sizes suitable for relevant results and analysis, as well as controlling the currently identified technical and methodological confounding factors. These research activities will surely discard the hypothesis of potential effectiveness or, on the contrary, redeemed a promise that remained latent for three decades.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Pacheco-Pantoja EL, Alvarez-Nemegyei J. Estatinas y osteoporosis: una promesa latente. Reumatol Clin. 2014;10:201–203.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:37 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Stimulation of bone formation in vitro and in rodents by statins" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Mundy" 1 => "R. Garrett" 2 => "S. Harris" 3 => "J. Chan" 4 => "D. Chen" 5 => "G. Rossini" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Science" "fecha" => "1999" "volumen" => "286" "paginaInicial" => "1946" "paginaFinal" => "1949" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10583956" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Regulation of human cranial osteoblast phenotype by FGF-2, FGFR-2 and BMP-2 signaling" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "P.J. Marie" 1 => "F. Debiais" 2 => "E. Haÿ" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Histol Histopathol" "fecha" => "2002" "volumen" => "17" "paginaInicial" => "877" "paginaFinal" => "885" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12168799" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statins, bone metabolism and treatment of bone catabolic diseases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "Y. Zhang" 1 => "A.D. Bradley" 2 => "D. Wang" 3 => "R.A. Reinhardt" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.phrs.2013.12.009" "Revista" => array:2 [ "tituloSerie" => "Pharmacol Res" "fecha" => "2014" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Protein prenylation: molecular mechanisms and functional consequences" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "F.L. Zhang" 1 => "P.J. Casey" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1146/annurev.bi.65.070196.001325" "Revista" => array:6 [ "tituloSerie" => "Annu Rev Biochem" "fecha" => "1996" "volumen" => "65" "paginaInicial" => "241" "paginaFinal" => "269" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8811180" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pitavastatin enhanced BMP-2 and osteocalcin expression by inhibition of Rho-associated kinase in human osteoblasts" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "K. Ohnaka" 1 => "S. Shimoda" 2 => "H. Nawata" 3 => "H. Shimokawa" 4 => "K. Kaibuchi" 5 => "Y. Iwamoto" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1006/bbrc.2001.5597" "Revista" => array:6 [ "tituloSerie" => "Biochem Biophys Res Commun" "fecha" => "2001" "volumen" => "287" "paginaInicial" => "337" "paginaFinal" => "342" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11554731" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Stimulation of ectopic bone formation in response to BMP-2 by Rho kinase inhibitor: a pilot study" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "H. Yoshikawa" 1 => "K. Yoshioka" 2 => "T. Nakase" 3 => "K. Itoh" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s11999-009-0976-6" "Revista" => array:6 [ "tituloSerie" => "Clin Orthop Relat Res" "fecha" => "2009" "volumen" => "467" "paginaInicial" => "3087" "paginaFinal" => "3095" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19609629" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Therapeutic levels of the hydroxmethylglutaryl-coenzyme A reductase inhibitor lovastatin activate ras signaling via phospholipase D2" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "K.J. Cho" 1 => "M.M. Hill" 2 => "S. Chigurupati" 3 => "G. Du" 4 => "R.G. Parton" 5 => "J.F. Hancock" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1128/MCB.00989-10" "Revista" => array:6 [ "tituloSerie" => "Mol Cell Biol" "fecha" => "2011" "volumen" => "31" "paginaInicial" => "1110" "paginaFinal" => "1120" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21245384" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Type I collagen promotes proliferation and osteogenesis of human mesenchymal stem cells via activation of ERK and Akt pathways" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "K.S. Tsai" 1 => "S.Y. Kao" 2 => "C.Y. Wang" 3 => "Y.J. Wang" 4 => "J.P. Wang" 5 => "S.C. Hung" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/jbm.a.32693" "Revista" => array:6 [ "tituloSerie" => "J Biomed Mater Res A" "fecha" => "2010" "volumen" => "94" "paginaInicial" => "673" "paginaFinal" => "682" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20336745" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statin suppresses apoptosis in osteoblastic cells: role of transforming growth factor-beta-Smad3 pathway" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "H. Kaji" 1 => "J. Naito" 2 => "Y. Inoue" 3 => "H. Sowa" 4 => "T. Sugimoto" 5 => "K. Chihara" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-0028-1082051" "Revista" => array:6 [ "tituloSerie" => "Horm Metab Res" "fecha" => "2008" "volumen" => "40" "paginaInicial" => "746" "paginaFinal" => "751" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18622892" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Partnership between DPC4 and SMAD proteins in TGF-beta signalling pathways" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "G. Lagna" 1 => "A. Hata" 2 => "A. Hemmati-Brivanlou" 3 => "J. Massagué" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/383832a0" "Revista" => array:6 [ "tituloSerie" => "Nature" "fecha" => "1996" "volumen" => "383" "paginaInicial" => "832" "paginaFinal" => "836" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8893010" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Simvastatin attenuates TNF-alpha-induced growth inhibition and apoptosis in murine osteoblastic MC3T3-E1 cells" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y.M. Yang" 1 => "W.D. Huang" 2 => "Q.M. Xie" 3 => "Z.R. Xu" 4 => "Q.J. Zhao" 5 => "X.M. Wu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00011-009-0082-y" "Revista" => array:6 [ "tituloSerie" => "Inflamm Res" "fecha" => "2010" "volumen" => "59" "paginaInicial" => "151" "paginaFinal" => "157" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19730988" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statins modulate the levels of osteoprotegerin/receptor activator of NFkappaB ligand mRNA in mouse bone-cell cultures" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "H. Kaji" 1 => "M. Kanatani" 2 => "T. Sugimoto" 3 => "K. Chihara" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1055/s-2005-870538" "Revista" => array:6 [ "tituloSerie" => "Horm Metab Res" "fecha" => "2005" "volumen" => "37" "paginaInicial" => "589" "paginaFinal" => "592" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16278780" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Simvastatin induces estrogen receptor-alpha expression in bone, restores bone loss, and decreases ER? Expression and uterine wet weight in ovariectomized rats" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "X. Li" 1 => "Q.S. Song" 2 => "J.Y. Wang" 3 => "Leng Hj" 4 => "Z.Q. Chen" 5 => "Z.J. Liu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00774-010-0231-y" "Revista" => array:6 [ "tituloSerie" => "J Bone Miner Metab" "fecha" => "2011" "volumen" => "29" "paginaInicial" => "396" "paginaFinal" => "403" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21063740" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Compactin suppresses bone resorption by inhibiting the fusion of prefusion osteoclasts and disrupting the actin ring in osteoclasts" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "J.T. Woo" 1 => "S. Kasai" 2 => "P.H. Stern" 3 => "K. Nagai" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1359/jbmr.2000.15.4.650" "Revista" => array:6 [ "tituloSerie" => "J Bone Miner Res" "fecha" => "2000" "volumen" => "15" "paginaInicial" => "650" "paginaFinal" => "662" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10780857" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "HMG-CoA reductase inhibitors increase BMD in type 2 diabetes mellitus patients" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "Y.S. Chung" 1 => "M.D. Lee" 2 => "S.K. Lee" 3 => "H.M. Kim" 4 => "L.A. Fitzpatrick" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.85.3.6476" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2000" "volumen" => "85" "paginaInicial" => "1137" "paginaFinal" => "1142" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10720052" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Simvastatin increases bone mineral density in hypercholesterolemic postmenopausal women" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G. Lupattelli" 1 => "A.M. Scarponi" 2 => "G. Vaudo" 3 => "D. Siepi" 4 => "A.R. Roscini" 5 => "F. Gemelli" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Metabolism" "fecha" => "2004" "volumen" => "53" "paginaInicial" => "744" "paginaFinal" => "748" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15164322" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "No effect of fluvastatin on the bone mineral density of children with minimal change glomerulonephritis and some focal mesangial cell proliferation, other than an ameliorating effect on their proteinuria" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "K. Kano" 1 => "K. Nishikura" 2 => "Y. Yamada" 3 => "O. Arisaka" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Clin Nephrol" "fecha" => "2005" "volumen" => "63" "paginaInicial" => "74" "paginaFinal" => "79" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15730048" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statins have additive effects to vertebral bone mineral density in combination with risedronate in hypercholesterolemic postmenopausal women" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "H.A. Tanriverdi" 1 => "A. Barut" 2 => "S. Sarikaya" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.ejogrb.2004.08.007" "Revista" => array:6 [ "tituloSerie" => "Eur J Obstet Gynecol Reprod Biol" "fecha" => "2005" "volumen" => "120" "paginaInicial" => "63" "paginaFinal" => "68" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15866088" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bone mineral density in statin users: a population-based analysis from a Spanish cohort" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.L. Hernández" 1 => "J.M. Olmos" 2 => "G. Romaña" 3 => "J. Martinez" 4 => "J. Castillo" 5 => "I. Yezerska" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00774-013-0481-6" "Revista" => array:6 [ "tituloSerie" => "J Bone Miner Metab" "fecha" => "2014" "volumen" => "32" "paginaInicial" => "184" "paginaFinal" => "191" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23784551" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Simvastatin increases serum osteocalcin concentration in patients treated for hypercholesterolaemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "M.H. Chan" 1 => "T.W. Mak" 2 => "R.W. Chiu" 3 => "C.C. Chow" 4 => "I.H. Chan" 5 => "C.W. Lam" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.86.9.8001" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2001" "volumen" => "86" "paginaInicial" => "4556" "paginaFinal" => "4559" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11549708" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The effect of fluvastatin on parameters of bone remodeling" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "N.H. Bjarnason" 1 => "B.J. Riis" 2 => "C. Christiansen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s001980170106" "Revista" => array:6 [ "tituloSerie" => "Osteoporos Int" "fecha" => "2001" "volumen" => "12" "paginaInicial" => "380" "paginaFinal" => "384" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11444086" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Short-term reduction in bone markers with high-dose simvastatin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "R.S. Rosenson" 1 => "C.C. Tangney" 2 => "C.B. Langman" 3 => "T.S. Parker" 4 => "D.M. Levine" 5 => "B.R. Gordon" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00198-005-1897-1" "Revista" => array:6 [ "tituloSerie" => "Osteoporos Int" "fecha" => "2005" "volumen" => "16" "paginaInicial" => "1272" "paginaFinal" => "1276" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16088363" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Short-term effects of atorvastatin on bone turnover in male patients with hypercholesterolemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "T. Majima" 1 => "Y. Komatsu" 2 => "A. Fukao" 3 => "K. Ninomiya" 4 => "T. Matsumura" 5 => "K. Nakao" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Endocr J" "fecha" => "2007" "volumen" => "54" "paginaInicial" => "145" "paginaFinal" => "151" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17185879" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Short-term effects of pitavastatin on biochemical markers of bone turnover in patients with hypercholesterolemia" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. Majima" 1 => "A. Shimatsu" 2 => "Y. Komatsu" 3 => "N. Satoh" 4 => "A. Fukao" 5 => "K. Ninomiya" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Intern Med" "fecha" => "2007" "volumen" => "46" "paginaInicial" => "1967" "paginaFinal" => "1973" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18084118" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of simvastatin treatment on bone mineral density and bone turnover in hypercholesterolemic postmenopausal women: a 1-year longitudinal study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Montagnani" 1 => "S. Gonnelli" 2 => "C. Cepollaro" 3 => "S. Pacini" 4 => "M.S. Campagna" 5 => "M.B. Franci" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Bone" "fecha" => "2003" "volumen" => "32" "paginaInicial" => "427" "paginaFinal" => "433" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12689687" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The impact of statin therapy on bone density changes in postmenopausal women" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "P. Svejda" 1 => "V. Soska" 2 => "M. Soucek" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Vnitr Lek" "fecha" => "2007" "volumen" => "53" "paginaInicial" => "1064" "paginaFinal" => "1070" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18072431" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of statins vs non-statin lipid-lowering therapy on bone formation and bone mineral density biomarkers in patients with hyperlipidemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S. Chuengsamarn" 1 => "S. Rattanamongkoulgul" 2 => "S. Suwanwalaikorn" 3 => "S. Wattanasirichaigoon" 4 => "L. Kaufman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bone.2009.12.023" "Revista" => array:6 [ "tituloSerie" => "Bone" "fecha" => "2010" "volumen" => "46" "paginaInicial" => "1011" "paginaFinal" => "1015" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20045497" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effect of pravastatin on frequency of fracture in the LIPID study: secondary analysis of a randomised controlled trial. Long-term intervention with pravastatin in ischaemic disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "I.R. Reid" 1 => "W. Hague" 2 => "J. Emberson" 3 => "J. Baker" 4 => "A. Tonkin" 5 => "D. Hunt" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Lancet" "fecha" => "2001" "volumen" => "357" "paginaInicial" => "509" "paginaFinal" => "512" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11229669" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Use of statins and risk of fractures" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "T.P. Van Staa" 1 => "S. Wegman" 2 => "F. de Vries" 3 => "B. Leufkens" 4 => "C. Cooper" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Am Med Assoc" "fecha" => "2001" "volumen" => "285" "paginaInicial" => "1850" "paginaFinal" => "1855" ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Relation of statin use and bone loss: a prospective population-based cohort study in early postmenopausal women" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J. Sirola" 1 => "J. Sirola" 2 => "R. Honkanen" 3 => "H. Kröger" 4 => "J.S. Jurvelin" 5 => "P. Mäenpää" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s001980200070" "Revista" => array:6 [ "tituloSerie" => "Osteoporos Int" "fecha" => "2002" "volumen" => "13" "paginaInicial" => "537" "paginaFinal" => "541" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12111013" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statin use, clinical fracture, and bone density in postmenopausal women: results from the Women's Health Initiative Observational Study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.Z. LaCroix" 1 => "J.A. Cauley" 2 => "M. Pettinger" 3 => "J. Hsia" 4 => "D.C. Bauer" 5 => "J. McGowan" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Intern Med" "fecha" => "2003" "volumen" => "139" "paginaInicial" => "97" "paginaFinal" => "104" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12859159" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hydroxymethylglutaryl-coenzyme A reductase inhibitors and osteoporosis: a meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "C. Hatzigeorgiou" 1 => "J.L. Jackson" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00198-004-1793-0" "Revista" => array:6 [ "tituloSerie" => "Osteoporos Int" "fecha" => "2005" "volumen" => "16" "paginaInicial" => "990" "paginaFinal" => "998" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15744453" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Statin use, bone mineral density, and fracture risk: Geelong Osteoporosis Study" "autores" => array:1 [ 0 => array:3 [ "colaboracion" => "GOS" "etal" => false "autores" => array:5 [ 0 => "J.A. Pasco" 1 => "M.A. Kotowicz" 2 => "M.J. Henry" 3 => "K.M. Sanders" 4 => "G.C. Nicholson" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arch Intern Med" "fecha" => "2002" "volumen" => "162" "paginaInicial" => "537" "paginaFinal" => "540" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11871921" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Use of statins and fracture: Results of 4 prospective studies and cumulative meta-analysis of observational studies and controlled trials" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.C. Bauer" 1 => "G.R. Mundy" 2 => "S.A. Jamal" 3 => "D.M. Black" 4 => "J.A. Cauley" 5 => "K.E. Ensrud" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1001/archinte.164.2.146" "Revista" => array:6 [ "tituloSerie" => "Arch Intern Med" "fecha" => "2004" "volumen" => "164" "paginaInicial" => "146" "paginaFinal" => "152" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14744837" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0175" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Influence of fluvastatin on bone formation induced by demineralized bone matrix in mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R. Galus" 1 => "P. Wlodarski" 2 => "K. Wlodarski" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Pharmacol Rep" "fecha" => "2006" "volumen" => "58" "paginaInicial" => "443" "paginaFinal" => "447" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16845222" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0180" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Distribution of lovastatin to bone and its effect on bone turnover in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S.B. Jadhav" 1 => "P.S. Narayana Murthy" 2 => "M.M. Singh" 3 => "G.K. Jain" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1211/jpp.58.11.0005" "Revista" => array:6 [ "tituloSerie" => "J Pharm Pharmacol" "fecha" => "2006" "volumen" => "58" "paginaInicial" => "1451" "paginaFinal" => "1458" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17132207" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "D. Williams" 1 => "J. Feely" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2165/00003088-200241050-00003" "Revista" => array:6 [ "tituloSerie" => "Clin Pharmacokinet" "fecha" => "2002" "volumen" => "41" "paginaInicial" => "343" "paginaFinal" => "370" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12036392" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/21735743/0000001000000004/v1_201406280041/S2173574314000938/v1_201406280041/en/main.assets" "Apartado" => array:4 [ "identificador" => "17335" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Editorial" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/21735743/0000001000000004/v1_201406280041/S2173574314000938/v1_201406280041/en/main.pdf?idApp=UINPBA00004M&text.app=https://reumatologiaclinica.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574314000938?idApp=UINPBA00004M" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 2 | 3 | 5 |
| 2024 October | 39 | 18 | 57 |
| 2024 September | 42 | 22 | 64 |
| 2024 August | 63 | 25 | 88 |
| 2024 July | 57 | 23 | 80 |
| 2024 June | 61 | 34 | 95 |
| 2024 May | 55 | 26 | 81 |
| 2024 April | 31 | 13 | 44 |
| 2024 March | 50 | 33 | 83 |
| 2024 February | 23 | 22 | 45 |
| 2024 January | 33 | 24 | 57 |
| 2023 December | 21 | 17 | 38 |
| 2023 November | 20 | 17 | 37 |
| 2023 October | 48 | 26 | 74 |
| 2023 September | 77 | 34 | 111 |
| 2023 August | 34 | 11 | 45 |
| 2023 July | 30 | 22 | 52 |
| 2023 June | 27 | 26 | 53 |
| 2023 May | 28 | 26 | 54 |
| 2023 April | 22 | 8 | 30 |
| 2023 March | 34 | 31 | 65 |
| 2023 February | 42 | 34 | 76 |
| 2023 January | 22 | 25 | 47 |
| 2022 December | 41 | 55 | 96 |
| 2022 November | 38 | 41 | 79 |
| 2022 October | 51 | 36 | 87 |
| 2022 September | 30 | 30 | 60 |
| 2022 August | 27 | 40 | 67 |
| 2022 July | 24 | 34 | 58 |
| 2022 June | 25 | 30 | 55 |
| 2022 May | 26 | 47 | 73 |
| 2022 April | 36 | 58 | 94 |
| 2022 March | 33 | 35 | 68 |
| 2022 February | 33 | 30 | 63 |
| 2022 January | 28 | 29 | 57 |
| 2021 December | 26 | 43 | 69 |
| 2021 November | 31 | 37 | 68 |
| 2021 October | 43 | 42 | 85 |
| 2021 September | 41 | 40 | 81 |
| 2021 August | 36 | 29 | 65 |
| 2021 July | 28 | 25 | 53 |
| 2021 June | 35 | 30 | 65 |
| 2021 May | 38 | 40 | 78 |
| 2021 April | 51 | 84 | 135 |
| 2021 March | 51 | 33 | 84 |
| 2021 February | 34 | 25 | 59 |
| 2021 January | 30 | 14 | 44 |
| 2020 December | 36 | 17 | 53 |
| 2020 November | 27 | 25 | 52 |
| 2020 October | 27 | 8 | 35 |
| 2020 September | 39 | 18 | 57 |
| 2020 August | 27 | 20 | 47 |
| 2020 July | 14 | 11 | 25 |
| 2020 June | 33 | 16 | 49 |
| 2020 May | 31 | 14 | 45 |
| 2020 April | 16 | 14 | 30 |
| 2020 March | 11 | 4 | 15 |
| 2019 January | 1 | 0 | 1 |
| 2018 May | 5 | 0 | 5 |
| 2018 April | 29 | 9 | 38 |
| 2018 March | 50 | 5 | 55 |
| 2018 February | 37 | 5 | 42 |
| 2018 January | 26 | 10 | 36 |
| 2017 December | 36 | 6 | 42 |
| 2017 November | 37 | 8 | 45 |
| 2017 October | 55 | 4 | 59 |
| 2017 September | 30 | 6 | 36 |
| 2017 August | 39 | 10 | 49 |
| 2017 July | 39 | 14 | 53 |
| 2017 June | 58 | 10 | 68 |
| 2017 May | 71 | 17 | 88 |
| 2017 April | 38 | 10 | 48 |
| 2017 March | 44 | 36 | 80 |
| 2017 February | 43 | 6 | 49 |
| 2017 January | 29 | 8 | 37 |
| 2016 December | 69 | 17 | 86 |
| 2016 November | 65 | 11 | 76 |
| 2016 October | 72 | 17 | 89 |
| 2016 September | 78 | 11 | 89 |
| 2016 August | 66 | 10 | 76 |
| 2016 July | 40 | 13 | 53 |
| 2015 December | 2 | 0 | 2 |
| 2015 September | 1 | 0 | 1 |
| 2015 August | 2 | 0 | 2 |
| 2015 July | 33 | 7 | 40 |
| 2015 June | 69 | 10 | 79 |
| 2015 May | 108 | 15 | 123 |
| 2015 April | 88 | 22 | 110 |
| 2015 March | 87 | 8 | 95 |
| 2015 February | 84 | 9 | 93 |
| 2015 January | 80 | 15 | 95 |
| 2014 December | 64 | 13 | 77 |
| 2014 November | 48 | 10 | 58 |
| 2014 October | 38 | 18 | 56 |
| 2014 September | 42 | 16 | 58 |
| 2014 August | 58 | 24 | 82 |
| 2014 July | 55 | 33 | 88 |
Show all
