Continuing medical education
Treatment of Paget's Disease of Bone
Tratamiento de la enfermedad ósea de Paget
Leticia Lojo Oliveira
, Antonio Torrijos Eslava
Corresponding author
Unidad Metabólica Ósea, Servicio de Reumatología, Hospital Universitario La Paz, Madrid, Spain
Read
10630
Timeswas read the article
3892
Total PDF
6738
Total HTML
Share statistics
array:24 [ "pii" => "S2173574312000159" "issn" => "21735743" "doi" => "10.1016/j.reumae.2011.06.006" "estado" => "S300" "fechaPublicacion" => "2012-07-01" "aid" => "349" "copyright" => "Elsevier España, S.L.. All rights reserved" "copyrightAnyo" => "2011" "documento" => "article" "crossmark" => 0 "subdocumento" => "sco" "cita" => "Reumatol Clin. 2012;8:220-4" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 4689 "formatos" => array:3 [ "EPUB" => 66 "HTML" => 3584 "PDF" => 1039 ] ] "Traduccion" => array:1 [ "es" => array:19 [ "pii" => "S1699258X11001872" "issn" => "1699258X" "doi" => "10.1016/j.reuma.2011.06.003" "estado" => "S300" "fechaPublicacion" => "2012-07-01" "aid" => "349" "copyright" => "Elsevier España, S.L." "documento" => "article" "crossmark" => 0 "subdocumento" => "sco" "cita" => "Reumatol Clin. 2012;8:220-4" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 44110 "formatos" => array:3 [ "EPUB" => 172 "HTML" => 41612 "PDF" => 2326 ] ] "es" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Formación médica continuada</span>" "titulo" => "Tratamiento de la enfermedad ósea de Paget" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "220" "paginaFinal" => "224" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Treatment of Paget's disease of bone" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Leticia Lojo Oliveira, Antonio Torrijos Eslava" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Leticia" "apellidos" => "Lojo Oliveira" ] 1 => array:2 [ "nombre" => "Antonio" "apellidos" => "Torrijos Eslava" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2173574312000159" "doi" => "10.1016/j.reumae.2011.06.006" "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/S2173574312000159?idApp=UINPBA00004M" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1699258X11001872?idApp=UINPBA00004M" "url" => "/1699258X/0000000800000004/v1_201305061922/S1699258X11001872/v1_201305061922/es/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2173574312000871" "issn" => "21735743" "doi" => "10.1016/j.reumae.2012.06.013" "estado" => "S300" "fechaPublicacion" => "2012-07-01" "aid" => "390" "copyright" => "Elsevier España, S.L." "documento" => "article" "crossmark" => 0 "subdocumento" => "sco" "cita" => "Reumatol Clin. 2012;8:225-6" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 10038 "formatos" => array:3 [ "EPUB" => 55 "HTML" => 9469 "PDF" => 514 ] ] "en" => array:11 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Images in Clinical Rheumatology</span>" "titulo" => "43-Year-Old-Male With a Right Pelvic Mass" "tienePdf" => "en" "tieneTextoCompleto" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "225" "paginaFinal" => "226" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Varón de 43 años con masa pélvica derecha" ] ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1142 "Ancho" => 1560 "Tamanyo" => 144294 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Pelvis CT: lysis of the medial or superior portion of the acetabulum extended to the iliac and superior pubic ramus, associated with a large soft tissue mass measuring 12<span class="elsevierStyleHsp" style=""></span>mm×74<span class="elsevierStyleHsp" style=""></span>mm×73<span class="elsevierStyleHsp" style=""></span>mm (arrow), infiltrating muscle.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Carmen Carrasco Cubero, Josefa Jiménez Arjona, Alfredo Michán Doña" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Carmen" "apellidos" => "Carrasco Cubero" ] 1 => array:2 [ "nombre" => "Josefa" "apellidos" => "Jiménez Arjona" ] 2 => array:2 [ "nombre" => "Alfredo" "apellidos" => "Michán Doña" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1699258X11003275" "doi" => "10.1016/j.reuma.2011.09.008" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1699258X11003275?idApp=UINPBA00004M" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574312000871?idApp=UINPBA00004M" "url" => "/21735743/0000000800000004/v1_201305061641/S2173574312000871/v1_201305061641/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2173574312000512" "issn" => "21735743" "doi" => "10.1016/j.reumae.2012.04.001" "estado" => "S300" "fechaPublicacion" => "2012-07-01" "aid" => "407" "copyright" => "Elsevier España, S.L." "documento" => "article" "crossmark" => 0 "subdocumento" => "sco" "cita" => "Reumatol Clin. 2012;8:216-9" "abierto" => array:3 [ "ES" => false "ES2" => false "LATM" => false ] "gratuito" => false "lecturas" => array:2 [ "total" => 4819 "formatos" => array:3 [ "EPUB" => 58 "HTML" => 3666 "PDF" => 1095 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Case Report</span>" "titulo" => "Type III Takayasu's Arteritis in a Pediatric Patient. Case Report and Review of the Literature" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "216" "paginaFinal" => "219" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Arteritis de Takayasu tipo III en un paciente pediátrico. Reporte de caso y revisión de la literatura" ] ] "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" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1312 "Ancho" => 2986 "Tamanyo" => 253985 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">(A) and (B) Angioplasty. Placement of 2 long stents, covering the area of severe stenosis. Postoperative gradient: none. Gradient of the renal stenosis: 10<span class="elsevierStyleHsp" style=""></span>mmHg. There was no procedure on the left subclavian or the renal arteries.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Karla Mendiola Ramírez, Astrid Cristina Portillo Rivera, Abraham Galicia Reyes, José Antonio García Montes, María del Rocío Maldonado Velázquez, Enrique Faugier Fuentes" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Karla" "apellidos" => "Mendiola Ramírez" ] 1 => array:2 [ "nombre" => "Astrid Cristina" "apellidos" => "Portillo Rivera" ] 2 => array:2 [ "nombre" => "Abraham" "apellidos" => "Galicia Reyes" ] 3 => array:2 [ "nombre" => "José Antonio" "apellidos" => "García Montes" ] 4 => array:2 [ "nombre" => "María del Rocío" "apellidos" => "Maldonado Velázquez" ] 5 => array:2 [ "nombre" => "Enrique" "apellidos" => "Faugier Fuentes" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S1699258X12000204" "doi" => "10.1016/j.reuma.2011.11.008" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1699258X12000204?idApp=UINPBA00004M" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574312000512?idApp=UINPBA00004M" "url" => "/21735743/0000000800000004/v1_201305061641/S2173574312000512/v1_201305061641/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Continuing medical education</span>" "titulo" => "Treatment of Paget's Disease of Bone" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "220" "paginaFinal" => "224" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Leticia Lojo Oliveira, Antonio Torrijos Eslava" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Leticia" "apellidos" => "Lojo Oliveira" "email" => array:1 [ 0 => "leticialojooliveira2@yahoo.es" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Antonio" "apellidos" => "Torrijos Eslava" ] ] "afiliaciones" => array:1 [ 0 => array:1 [ "entidad" => "Unidad Metabólica Ósea, Servicio de Reumatología, Hospital Universitario La Paz, Madrid, Spain" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento de la enfermedad ósea de Paget" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Paget's disease of bone (PD), also known as osteitis deformans, was first described in 1876 by the English surgeon Paget.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> It is a focal skeletal disorder in which bone remodeling is accelerated, with an initial increase in bone resorption followed by excessive osteoblastic activity. As a result, there is deformity and enlargement of the bone with a defective and disorganized pattern (plexiform bone) and therefore more susceptible to fractures and deformities.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Its etiology is unknown. The current etiopathogenic hypothesis is complex, and includes an initial sensitization phenomenon by an environmental agent of the appropriate genetic determinant, leading to the development of the disease.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Its diagnosis is rare before age 40, and in most series predominates in males. Its geographical distribution is uneven with areas of high prevalence, with familial aggregation detected in most series.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Most patients are asymptomatic, with the predominant form being polyostotic involvement. The main symptoms, when present, are bone pain and deformity. The diagnosis is made with imaging by plain radiography, and scintigraphy with Technecium<span class="elsevierStyleSup">99</span>, something that enables the making of a topographic map of the disease. Other imaging techniques are resorted to in cases that raise diagnostic doubts. The evaluation of biochemical markers of bone turnover provides indirect information of both disease activity and the therapeutic response.</p><p id="par0025" class="elsevierStylePara elsevierViewall">On the basis of pathogenic features of PD, treatment with antiresorptive drugs is used to achieve normalization of bone turnover. Since the introduction of bisphosphonates in 1970, these agents have become the treatment of choice<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4–13</span></a> because of their better efficacy and safety profile compared to then used calcitonin.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Targets and Therapeutic Indications</span><p id="par0030" class="elsevierStylePara elsevierViewall">Before discussing the main drugs available and their individual characteristics, let us define the goals of treatment and the main indications.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The goal of treatment is control of symptoms and normalization of remodeling markers, all without altering the mineralization and normalizing bone structure.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> What we are trying to achieve is to prevent future complications with early therapeutic intervention, a fact that at present has no evidence to support it.</p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Treatment</span><p id="par0040" class="elsevierStylePara elsevierViewall">There are widely accepted guidelines, including consensus recommendations,<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,5,7,9–14</span></a> as described below:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">•</span><p id="par0045" class="elsevierStylePara elsevierViewall">Symptomatic patients (bone pain from the disease or secondary to fragility fractures, neurological compression syndromes, heart failure due to treatment).</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">•</span><p id="par0050" class="elsevierStylePara elsevierViewall">Preoperative treatment of elective surgery on the Pagetic bone to prevent intraoperative bleeding complications.</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">•</span><p id="par0055" class="elsevierStylePara elsevierViewall">Hypercalcemia. Appears infrequently and occurs in patients with extensive involvement and after periods of prolonged immobilization.</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">•</span><p id="par0060" class="elsevierStylePara elsevierViewall">Impact of critical areas susceptible to developing severe complications (long bones, skull base, spine especially above L2 and adjacent to large joints, lytic lesions).</p></li></ul></p><p id="par0065" class="elsevierStylePara elsevierViewall">The dilemma of therapeutic intervention in PD is present in asymptomatic patients with biochemical or imaging activity. Treatment aims to prevent development of complications with early intervention. Recommendations are based on studies of low statistical power and theoretical considerations. In fact in 2010, the PRISM<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> study was published, comparing two treatment strategies with bisphosphonates; an aggressive approach in which patients were treated when there was alkaline phosphatase elevation whether symptomatic or not, and the outcome being the primary biochemical normalization; and another, treating only symptomatic patients. The intention was to determine whether an intensive strategy in asymptomatic patients but with biochemical activity prevented the development of further complications. No differences were found between groups in the prosthetic hip replacement numbers, number of fractures, hearing loss or improved quality of life. The study has limitations in design and a limited follow-up time (3 year on average), as well the fact that zoledronic acid, the most potent drug available at present, was not evaluated.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Therefore, well-designed studies are needed to determine long-term prevention of the development of complications in PD and to provide data that may condition decisive therapeutic decisions.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Anyway, even despite the lack of evidence, the tendency is to treat patients who have greater risk of future complications.</p></span></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Pharmacotherapy</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Modulators of the Activity</span><p id="par0080" class="elsevierStylePara elsevierViewall">The mainstay of treatment of the PD is the use of antiresorptive agents in order to reduce high bone turnover and osteoclast activity. Over the years various drugs have been used, but since the introduction of bisphosphonates in 1970, they have become the antiresorptive treatment of choice.</p><p id="par0085" class="elsevierStylePara elsevierViewall">All bisphosphonates share a common chemical structure (two phosphate molecules attached to a carbon atom). They are synthetic analogs of pyrophosphate with antiresorptive potency, and act by reducing bone remodeling and resorption. The effect is achieved by both osteoclast differentiation of stem cells as common precursor, promoting apoptosis of mature osteoclasts. According to their structure, they are classified depending on whether they contain an amino group or not (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), with amino-bisphosphonates having demonstrated a better efficacy and safety profile.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">Bisphosphonates approved for use in the PD marketed in Spain are: pamidronate, risedronate and zoledronic acid (amino) and non-amino group drugs such as etidronate and tiludronate (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Other bisphosphonates have demonstrated efficacy in Paget's disease but have not been marketed for this indication in Spain (alendronate, ibandronate, neridronate, olpadronate and clodronate).<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">•</span><p id="par0095" class="elsevierStylePara elsevierViewall">First generation bisphosphonates<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0030"><p id="par0100" class="elsevierStylePara elsevierViewall">Non-amino bisphosphonates have been displaced by the amino-bisphosphonates as the treatment of choice, and the former are used only in case of contraindication to the latter compounds.</p></li><li class="elsevierStyleListItem" id="lsti0120"><p id="par0255" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Etidronate</span> was the first bisphosphonate used in PD and showed a greater reduction in bone turnover than calcitonin, the antiresorptive agent used at that time.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> However, the detection of alterations in bone mineralization secondary to the use of etidronate limited the dose and duration of use (not to exceed 6 months). Early reactivation of the disease and the emergence of resistance in some patients<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> were also noted.</p></li><li class="elsevierStyleListItem" id="lsti0125"><p id="par0260" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Tiludronate</span> proved superior to etidronate without the appearance of alterations in mineralization, achieving a reduction of alkaline phosphatase between 30.5% and 76.1% which remained at 12 months in up to 69% of patients.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18–22</span></a></p></li><li class="elsevierStyleListItem" id="lsti0130"><p id="par0265" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleUnderline">Clodronate</span> has no indication for PD in Spain. The efficacy is similar to that of etidronate, although with longer periods of remission. It does not have effects on bone mineralization.<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23,24</span></a></p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">•</span><p id="par0105" class="elsevierStylePara elsevierViewall">Amino-bisphosphonates<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0040"><p id="par0110" class="elsevierStylePara elsevierViewall">The treatment of Paget's disease suffered a shift in 1979 with the publication of a study using oral<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a><span class="elsevierStyleUnderline">pamidronate</span>. An antiresorptive, it led to rapid restoration of normal bone formation. This study led to a series of publications on the use of pamidronate in PD, both orally and intravenously, demonstrating its superiority over other non-aminated bisphosphonates.<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26–31</span></a> The currently approved regimen is intravenous (doses in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). No alterations in bone mineralization have been described, but resistance has been detected on those patients retreated with this drug.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p></li><li class="elsevierStyleListItem" id="lsti0045"><p id="par0115" class="elsevierStylePara elsevierViewall">Later came the development of another amino-bisphosphonate, <span class="elsevierStyleUnderline">alendronate</span>. Its efficacy was established in two randomized clinical trials, one alone and another vs placebo,<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> or etidronate,<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> showing a normalization of the alkaline phosphatase in 60%–70% of patients at 6 months. In 2004, a comparative study of oral alendronate vs IV pamidronate<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> was published. No differences were found between both treatment groups when it came to patients not receiving bisphosphonates, but alendronate was superior in patients previously treated with pamidronate. Alendronate has no indication for PD in our country.</p></li></ul></p><p id="par0120" class="elsevierStylePara elsevierViewall">In parallel with alendronate, <span class="elsevierStyleUnderline">risedronate</span> was developed, demonstrating its efficacy in open<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">36–38</span></a> studies and against etidronate,<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> reducing alkaline phosphatase in 66%–80%. Currently the amino-bisphosphonate risedronate is the only oral drug indicated in our country for PD.</p><p id="par0125" class="elsevierStylePara elsevierViewall">The most recently introduced bisphosphonate in the treatment of PD is <span class="elsevierStyleUnderline">zoledronic acid</span>. It is a bisphosphonate that has shown affinity for hydroxyapatite in vitro and the most potent antiresorptive we currently have.<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40,41</span></a> It is administered as a single intravenous infusion of 5<span class="elsevierStyleHsp" style=""></span>mg. Two randomized trials comparing single infusion zoledronic acid with risedronate oral<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> exist. Zoledronic acid improved response at 6 months in 96% of responding patients compared to 74.3% in the risedronate group, and was associated with a faster and maintained response. These results will be confirmed in a 2 and 5-year extension study.</p><p id="par0130" class="elsevierStylePara elsevierViewall">In 2007, the results of a study comparing different IV bisphosphonates<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> were published. Compared to pamidronate, another bisphosphonate indicated intravenously in our country for PD, zoledronic acid was more effective and associates with an earlier response, with more pamidronate infusions required and with the development of resistance to treatment. Further studies are needed to expand the evidence, but for now zoledronic acid is better, with results in both induction and maintenance of remission.</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">•</span><p id="par0135" class="elsevierStylePara elsevierViewall">Other drugs<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0055"><p id="par0140" class="elsevierStylePara elsevierViewall">Although the new bisphosphonates are drugs with a good safety profile and relatively well tolerated, there are situations in which we cannot use them.</p></li><li class="elsevierStyleListItem" id="lsti0060"><p id="par0145" class="elsevierStylePara elsevierViewall">In these cases the peptide hormone calcitonin, capable of inhibiting bone resorption, could be useful. It was used in the treatment of PD, but relapses after discontinuation of treatment and a plateau effect after approximately 4–6 months of treatment, relegated it to the backburner after the appearance of bisphosphonates.</p></li><li class="elsevierStyleListItem" id="lsti0065"><p id="par0150" class="elsevierStylePara elsevierViewall">Other therapies such as gallium nitrate are used only in patients with serious complications or bisphosphonate resistance because it has a limited effect and frequent<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> recurrences. Mithramycin is no longer used due to its renal, bone marrow and liver<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> toxicity.</p></li></ul></p></li><li class="elsevierStyleListItem" id="lsti0070"><span class="elsevierStyleLabel">•</span><p id="par0155" class="elsevierStylePara elsevierViewall">Calcium and vitamin D<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0075"><p id="par0160" class="elsevierStylePara elsevierViewall">Another fundamental aspect in the treatment of PD is calcium (1000<span class="elsevierStyleHsp" style=""></span>mg) and vitamin D (400–800<span class="elsevierStyleHsp" style=""></span>IU) supplementation in patients receiving antiresorptive therapy to prevent hypocalcemia and secondary hyperparathyroidism.</p></li><li class="elsevierStyleListItem" id="lsti0080"><p id="par0165" class="elsevierStylePara elsevierViewall">The standard dose is indicated, but must be individualized by laboratory testing, enhancing supplementation in the case of zoledronic acid in the days before and after its infusion.</p></li></ul></p></li></ul></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Symptoms</span><p id="par0170" class="elsevierStylePara elsevierViewall">Apart from specific treatment, we must effectively manage symptoms. The main symptom is pain, which may not always be derived from the activity of the disease, but may be secondary to complications and localized lesions. It is mainly treated with NSAIDs and analgesics, with tricyclic antidepressants being useful in some cases.</p><p id="par0175" class="elsevierStylePara elsevierViewall">On the other hand, we should not forget orthotic treatment, walking and hearing aids, canes, etc., which may help improve the quality of life of patients.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Surgery</span><p id="par0180" class="elsevierStylePara elsevierViewall">There are five main indications for surgical treatment<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,46</span></a>:<ul class="elsevierStyleList" id="lis0035"><li class="elsevierStyleListItem" id="lsti0085"><span class="elsevierStyleLabel">1.</span><p id="par0185" class="elsevierStylePara elsevierViewall">Fractures.</p></li><li class="elsevierStyleListItem" id="lsti0090"><span class="elsevierStyleLabel">2.</span><p id="par0190" class="elsevierStylePara elsevierViewall">Deformity: that cause pain when they are difficult to control or associated with bone fissures, corrected through the use of osteotomy.</p></li><li class="elsevierStyleListItem" id="lsti0095"><span class="elsevierStyleLabel">3.</span><p id="par0195" class="elsevierStylePara elsevierViewall">Pagetic arthropathy: arthroplasty when symptoms are not effectively controlled with medical treatment.</p></li><li class="elsevierStyleListItem" id="lsti0100"><span class="elsevierStyleLabel">4.</span><p id="par0200" class="elsevierStylePara elsevierViewall">Entrapment neuropathies and myelopathies.</p></li><li class="elsevierStyleListItem" id="lsti0105"><span class="elsevierStyleLabel">5.</span><p id="par0205" class="elsevierStylePara elsevierViewall">Cancer.</p></li></ul></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Monitoring of Therapeutic Response</span><p id="par0210" class="elsevierStylePara elsevierViewall">Biomarkers of bone turnover indirectly estimate the activity of the disease<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47–49</span></a> and are therefore used in the assessment of treatment response in conjunction with the clinical response. Currently, despite the development of new markers, total alkaline phosphatase (TAP) remains the marker of choice for monitoring response to treatment.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,5,7,9,50,51</span></a> Historically, therapeutic response has been defined as a decrease of at least 25% of TAP; however, with current drugs, most studies measuring response set their objective as the normalization of biochemical markers or alternatively, as the decrease of at least 75% of initial TAP.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">However, and given the spectrum of presentations of PD, there are cases where other markers are more useful than TAP. In patients with monostotic involvement with normal TAP or patients with liver disease, the use of more sensitive markers such as alkaline phosphatase (AP) and the aminoterminal propeptide of procollagen type I (APPPI) is recommended.<a class="elsevierStyleCrossRefs" href="#bib0250"><span class="elsevierStyleSup">50,51</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Regarding the role of bone scintigraphy in monitoring therapeutic response, it has been relegated to isolated cases in which the patient is exposed to radiation and there is a delay of approximately 6 months with respect to the biochemical response. In patients with monostotic PD and normal bone turnover markers at baseline, it could be useful from 6 to 12 months after treatment.</p><p id="par0225" class="elsevierStylePara elsevierViewall">As for biomarker monitoring intervals should be individualized based on treatment and individual patient characteristics. A possibility would be the quarterly analytical monitoring the first 6 months and then every 6 months.<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4,5</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Retreatment</span><p id="par0230" class="elsevierStylePara elsevierViewall">The need for a new cycle of treatment occurs when there is a new increase of bone remodeling. At the onset of the disease or after the increase of the biomarkers discussed in the previous section, it is important to determine parameters that measure activity. Therefore, and according to the available evidence,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> we recommend a new course of treatment in cases of:<ul class="elsevierStyleList" id="lis0040"><li class="elsevierStyleListItem" id="lsti0110"><span class="elsevierStyleLabel">•</span><p id="par0235" class="elsevierStylePara elsevierViewall">Recurrence of symptoms and/or</p></li><li class="elsevierStyleListItem" id="lsti0115"><span class="elsevierStyleLabel">•</span><p id="par0240" class="elsevierStylePara elsevierViewall">Increased alkaline phosphatase above normal, or more than 25% of the nadir reached.</p></li></ul></p><p id="par0245" class="elsevierStylePara elsevierViewall">To clarify, since the effect of bisphosphonate treatment usually appears 3–6 months after onset of treatment, it is prudent to wait 6 months before determining the need for a new therapeutic intervention.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle">Disclosures</span><p id="par0250" class="elsevierStylePara elsevierViewall">The authors have no disclosures to make.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:2 [ "identificador" => "xres125803" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec113091" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres125804" "titulo" => "Resumen" ] 3 => array:2 [ "identificador" => "xpalclavsec113090" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Targets and Therapeutic Indications" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Treatment" ] ] ] 6 => array:3 [ "identificador" => "sec0020" "titulo" => "Pharmacotherapy" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Modulators of the Activity" ] ] ] 7 => array:2 [ "identificador" => "sec0030" "titulo" => "Symptoms" ] 8 => array:2 [ "identificador" => "sec0035" "titulo" => "Surgery" ] 9 => array:2 [ "identificador" => "sec0040" "titulo" => "Monitoring of Therapeutic Response" ] 10 => array:2 [ "identificador" => "sec0045" "titulo" => "Retreatment" ] 11 => array:2 [ "identificador" => "sec0050" "titulo" => "Disclosures" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2011-05-30" "fechaAceptado" => "2011-06-09" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec113091" "palabras" => array:4 [ 0 => "Paget's disease of bone" 1 => "Osteitis deformans" 2 => "Treatment" 3 => "Bisphosphonates" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec113090" "palabras" => array:4 [ 0 => "Enfermedad ósea de Paget" 1 => "Osteítis deformante" 2 => "Tratamiento" 3 => "Bifosfonatos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Paget's disease of bone is the paradigm of bone focal distortion with accelerated bone turnover. Over the years, a number of different drugs have been used to control its activity but, since bisphosphonates were introduced for the treatment of the disease, they have become the preferred treatment. This review will update the therapeutic indications, available drugs and therapeutic response monitoring.</p>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La enfermedad ósea de Paget es el paradigma de alteración focal esquelética con remodelado óseo acelerado. A lo largo de los años se han utilizado diferentes fármacos para el control de la actividad pero, desde la introducción de los bifosfonatos en la terapéutica de esta enfermedad, éstos se han convertido en el tratamiento de elección. A lo largo de esta revisión se abordarán de manera actualizada las indicaciones terapéuticas, los fármacos disponibles y la monitorización de la respuesta.</p>" ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara">Please, cite this article as: Lojo Oliveira L, Torrijos Eslava A. Tratamiento de la enfermedad ósea de Paget. Reumatol Clin. 2012;8:220–4.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Non-Aminated Bisphosphonates \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Aminated Bisphosphonates \t\t\t\t\t\t\n \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">EtidronateTiludronateClodronate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">PamidronateAlendronateRisedronateIbandronateNeridronateOlpadronateZolendronic acid \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab212311.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Classification of Bisphosphonates According to Their Amino Group.</p>" ] ] 1 => array:7 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Etidronate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5<span class="elsevierStyleHsp" style=""></span>mg/kg/day, 6 months, oral \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Tiludronate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">400<span class="elsevierStyleHsp" style=""></span>mg/day, 3 months, oral \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Risedronate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30<span class="elsevierStyleHsp" style=""></span>mg/day 2 months, oral \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pamidronate \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30<span class="elsevierStyleHsp" style=""></span>mg/week (6 doses) or a first dose of 30<span class="elsevierStyleHsp" style=""></span>mg then 60<span class="elsevierStyleHsp" style=""></span>mg/2 week (3 doses) (total dose 180–210<span class="elsevierStyleHsp" style=""></span>mg) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Zolendronic acid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5<span class="elsevierStyleHsp" style=""></span>mg IV single dose \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab212310.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Bisphosphonate Doses Approved in Spain for PD.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:51 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "On a form of chronic inflammation of bone (osteítis deformans)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J. Paget" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Med Chir Trans" "fecha" => "1877" "volumen" => "60" "paginaInicial" => "37" "paginaFinal" => "64" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20896492" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pathogenesis of Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "S.H. Ralston" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bone.2008.06.015" "Revista" => array:6 [ "tituloSerie" => "Bone" "fecha" => "2008" "volumen" => "43" "paginaInicial" => "819" "paginaFinal" => "825" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18672105" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Frequency and characteristics of the familial aggregation in Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A. Morales Piga" 1 => "J. Rey Rey" 2 => "J.M. García Sagredo" 3 => "G. López-Abente" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Bone Miner Res" "fecha" => "1995" "volumen" => "10" "paginaInicial" => "1" "paginaFinal" => "8" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A clinical approach to diagnosis and management of Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "K.W. Lyles" 1 => "F.R. Siris" 2 => "F.R. Singer" 3 => "P.J. Meunier" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1359/jbmr.2001.16.8.1379" "Revista" => array:6 [ "tituloSerie" => "J Bone Miner Res" "fecha" => "2001" "volumen" => "16" "paginaInicial" => "1379" "paginaFinal" => "1387" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11499860" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Guidelines on the management of Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "P.L. Selby" 1 => "M.W. Davie" 2 => "S.H. Ralston" 3 => "M.D. Stone" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Bone" "fecha" => "2002" "volumen" => "31" "paginaInicial" => "366" "paginaFinal" => "373" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12231408" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J.P. Walsh" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Med J Aust" "fecha" => "2004" "volumen" => "181" "paginaInicial" => "262" "paginaFinal" => "265" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15347275" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M.P. Whyte" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMcp060278" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2006" "volumen" => "355" "paginaInicial" => "593" "paginaFinal" => "600" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16899779" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Paget disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "G.D. Roodman" 1 => "J.J. Windle" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI24281" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "2005" "volumen" => "115" "paginaInicial" => "200" "paginaFinal" => "208" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15690073" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Medical management of Paget's disease of bone: indications for treatment and review of current therapies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "E.S. Siris" 1 => "K.W. Lyles" 2 => "F.R. Singer" 3 => "P.J. Meunier" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1359/jbmr.06s218" "Revista" => array:7 [ "tituloSerie" => "J Bone Miner Res" "fecha" => "2006" "volumen" => "21" "numero" => "Suppl. 2" "paginaInicial" => "P94" "paginaFinal" => "P98" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17229018" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Guidelines for the diagnosis and management of Paget's disease: a UK perspective" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "P.L. Selby" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Bone Miner Res" "fecha" => "2006" "volumen" => "21" "numero" => "Suppl. 2" "paginaInicial" => "92" "paginaFinal" => "93" ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Guidelines for diagnosis and management of Paget's disease of bone in Japan" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "S. Takata" 1 => "J. Hashimoto" 2 => "K. Nakatsuka" 3 => "N. Yoshimura" 4 => "K. Yoh" 5 => "I. Ohno" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00774-006-0696-x" "Revista" => array:6 [ "tituloSerie" => "J Bone Miner Metab" "fecha" => "2006" "volumen" => "24" "paginaInicial" => "359" "paginaFinal" => "367" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16937267" "web" => "Medline" ] ] ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "A physician's guide. Guide to the management of Paget's disease of bone. A publication of the Paget foundation. For Paget's disease of bone and related disorders [accessed April 2011]. Available from: <a class="elsevierStyleInterRef" href="http://www.paget.org/">http://www.paget.org</a>." ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Management of patients with Paget's disease: a consensus document of the Belgian Bone Club" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.P. Devogelaer" 1 => "P. Bergmann" 2 => "J.J. Body" 3 => "Y. Boutsen" 4 => "S. Goemaere" 5 => "J.M. Kaufman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00198-008-0629-8" "Revista" => array:6 [ "tituloSerie" => "Osteoporos Int" "fecha" => "2008" "volumen" => "19" "paginaInicial" => "1109" "paginaFinal" => "1117" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18504638" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Therapeutic strategy in Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "P.J. Meunier" 1 => "E. Vignot" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Bone" "fecha" => "1995" "volumen" => "17" "numero" => "Suppl. 5" "paginaInicial" => "489S" "paginaFinal" => "491S" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8573424" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Randomized trial of intensive bisphosphonate treatment versus symptomatic management in Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A.L. Langston" 1 => "M.K. Campbell" 2 => "W.D. Fraser" 3 => "G.S. MacLennan" 4 => "P.L. Selby" 5 => "S.H. Ralston" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1359/jbmr.090709" "Revista" => array:6 [ "tituloSerie" => "J Bone Miner Res" "fecha" => "2010" "volumen" => "25" "paginaInicial" => "20" "paginaFinal" => "31" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19580457" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Influence of disodium etidronate on clinical and laboratory manifestations of Paget's disease of bone (osteitis deformans)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "R.D. Altman" 1 => "C.C. Johnston" 2 => "M.R. Khairi" 3 => "H. Wellman" 4 => "A.N. Serafini" 5 => "R.R. Sankey" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJM197312272892601" "Revista" => array:7 [ "tituloSerie" => "N Engl J Med" "fecha" => "1973" "volumen" => "289" "paginaInicial" => "1379" "paginaFinal" => "1384" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/4201876" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0090825896900025" "estado" => "S300" "issn" => "00908258" ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sodium etidronate in the treatment of Paget's disease of bone. A study of long-term results" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "M.R. Khairi" 1 => "R.D. Altman" 2 => "G.P. De Rosa" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Ann Intern Med" "fecha" => "1977" "volumen" => "87" "paginaInicial" => "656" "paginaFinal" => "663" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/412450" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparative prospective, double-blind, multicenter study of the efficacy of tiludronate and etidronato in the treatment of Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "C. Roux" 1 => "C. Gennari" 2 => "J. Farrerons" 3 => "J.P. Devogelaer" 4 => "H. Mulder" 5 => "H.P. Kruse" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "1995" "volumen" => "38" "paginaInicial" => "851" "paginaFinal" => "858" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7779130" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Tiludronate therapy Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M.R. McClung" 1 => "C.K. Tou" 2 => "N.H. Goldstein" 3 => "C. Picot" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Bone" "fecha" => "1995" "volumen" => "17" "numero" => "Suppl. 5" "paginaInicial" => "S493" "paginaFinal" => "S496" ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A double-blind, multicentre, placebo-controlled study of tiludonate in Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "W.D. Fraser" 1 => "T.C. Stamp" 2 => "R.A. Creek" 3 => "J.P. Sawyer" 4 => "C. Picot" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Postgrad Med J" "fecha" => "1997" "volumen" => "73" "paginaInicial" => "496" "paginaFinal" => "502" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9307742" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Factores que determinan la intensidad de la respuesta al tratamiento con tiludronato en la enfermedad de Paget" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A. Morales" 1 => "V. Abraira" 2 => "J.S. Rey" 3 => "S. Abajo" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Med Clin (Barc)" "fecha" => "1998" "volumen" => "110" "paginaInicial" => "254" "paginaFinal" => "258" ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Respuesta al tiludronato de la enfermedad de Paget (resumen)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A. Torrijos" 1 => "F. Gamero" 2 => "J. García" 3 => "J. Fernández" 4 => "G. Diaz" 5 => "E. Marín" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rev Esp Reumatol" "fecha" => "2002" "volumen" => "29" "paginaInicial" => "246" "paginaFinal" => "247" ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Biochemical and clinical responses to dichloroethylene diphosphonate (CI2MDP) in Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.L. Douglas" 1 => "T. Duckworth" 2 => "J.A. Kanis" 3 => "D. Preston" 4 => "D.J. Beard" 5 => "T.W.D. Smith" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "1980" "volumen" => "23" "paginaInicial" => "1185" "paginaFinal" => "1192" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6448604" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Long term effects of dichloromethylene diphosphonate in Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P.D. Delmas" 1 => "M.C. Chapuy" 2 => "E. Vignon" 3 => "S. Charon" 4 => "D. Briancon" 5 => "C. Alexandre" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem-54-4-837" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "1982" "volumen" => "54" "paginaInicial" => "837" "paginaFinal" => "844" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6460781" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Treatment of Paget's disease with (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "O.L.M. Frijilink" 1 => "J. te Velde" 2 => "O.L.M. Bijvoet" 3 => "G. Heynen" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Lancet" "fecha" => "1979" "paginaInicial" => "799" "paginaFinal" => "803" ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "APD in Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "O.L.M. Bijvoet" 1 => "W.B. Frijlink" 2 => "K. Jie" 3 => "H. Van der Linden" 4 => "C.J.L.M. Meijer" 5 => "H. Mulder" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "1980" "volumen" => "23" "paginaInicial" => "1193" "paginaFinal" => "1204" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6448605" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Quantitative bone scintigraphy in Paget's disease treated with APD" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "C.J.L.R. Vellenga" 1 => "E.K.J. Pauwels" 2 => "O.L.M. Bijvoet" 3 => "W.B. Frijlink" 4 => "J.D. Mulder" 5 => "J. Hermans" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1259/0007-1285-58-696-1165" "Revista" => array:6 [ "tituloSerie" => "Br J Radiol" "fecha" => "1985" "volumen" => "58" "paginaInicial" => "1165" "paginaFinal" => "1172" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3842627" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Paget's disease of bone: early and late responses to three different modes of treatment with aminohydroxypropylidene bisphosphonate (APD)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "H.I.J. Harinck" 1 => "S.E. Papapoulos" 2 => "H.J. Blanksma" 3 => "A.J. Moolenaar" 4 => "P. Vermeij" 5 => "O.L.M. Bijvoet" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "BMJ" "fecha" => "1987" "volumen" => "295" "paginaInicial" => "1301" "paginaFinal" => "1305" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3120987" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effective oral treatment of severe Paget's disease of bone with APD; a comparison with combined calcitonin and EHDP" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T.R.C. Fraser" 1 => "H.K. Ibbertson" 2 => "I.M. Holdaway" 3 => "M. Rutland" 4 => "A. King" 5 => "G. Dodd" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Aust N Z J Med" "fecha" => "1984" "volumen" => "14" "paginaInicial" => "811" "paginaFinal" => "818" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6442563" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Radiological assessment of Paget's disease of bone after treatment with bisphosphonates EHDP and APD" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "J.W. Dodd" 1 => "H.K. Ibbertson" 2 => "T.R.C. Fraser" 3 => "I.M. Holdaway" 4 => "D. Wattie" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1259/0007-1285-60-717-849" "Revista" => array:6 [ "tituloSerie" => "Br J Radiol" "fecha" => "1987" "volumen" => "60" "paginaInicial" => "849" "paginaFinal" => "859" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3117159" "web" => "Medline" ] ] ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Intravenous pamidronate: evolution of an effective treatment strategy" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D.C. Anderson" 1 => "P.C. Richardson" 2 => "J. Kinsley-Brown" 3 => "A.J. Freemont" 4 => "S. Hollis" 5 => "J. Denton" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Semin Arthritis Rheum" "fecha" => "1994" "volumen" => "23" "paginaInicial" => "273" "paginaFinal" => "275" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8009254" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bisphosphonate resistance in Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "F. Joshua" 1 => "M. Epstein" 2 => "G. Major" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/art.11136" "Revista" => array:5 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "2003" "volumen" => "48" "paginaInicial" => "2321" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12905487" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Biochemical and radiologic improvement in Paget's disease of bone treated with alendronate-a randomized, placebo-controlled trial" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "I.R. Reid" 1 => "G.C. Nicholson" 2 => "R.S. Weinstein" 3 => "D.J. Hosking" 4 => "T. Cundy" 5 => "M.A. Kotowicz" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Med" "fecha" => "1996" "volumen" => "101" "paginaInicial" => "341" "paginaFinal" => "348" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8873503" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparative study of alendronate versus etidronate for the treatment of Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Siris" 1 => "R.S. Weinstein" 2 => "R. Altman" 3 => "J.M. Conte" 4 => "M. Favus" 5 => "A. Lombardi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.81.3.8772558" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "1996" "volumen" => "81" "paginaInicial" => "961" "paginaFinal" => "967" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8772558" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0175" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A randomized clinical trial comparing oral alendronate and intravenous pamidronate for the treatment of Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.P. Walsh" 1 => "L.C. Ward" 2 => "G.O. Stewart" 3 => "R.K. Will" 4 => "R.A. Criddle" 5 => "R.L. Prince" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bone.2003.12.011" "Revista" => array:5 [ "tituloSerie" => "Bone" "fecha" => "2004" "volumen" => "34" "paginaInicial" => "747" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15050907" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0180" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Paget's-disease of bone-reduction of disease activity with oral risedronate" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "D.J. Hosking" 1 => "R.A. Eusebio" 2 => "A.A. Chines" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Bone" "fecha" => "1998" "volumen" => "22" "paginaInicial" => "51" "paginaFinal" => "55" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9437513" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Risedronate, a highly effective oral agent in the treatment of patients with severe Paget's-disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "F.R. Singer" 1 => "T.L. Clemens" 2 => "R.A. Eusebio" 3 => "P.J. Bekker" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.83.6.4871" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "1998" "volumen" => "83" "paginaInicial" => "1906" "paginaFinal" => "1910" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9626117" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0190" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Risedronate in the treatment of Paget's-disease of bone-an open label, multicenter study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.S. Siris" 1 => "A.A. Chines" 2 => "R.D. Altman" 3 => "J.P. Brown" 4 => "C.C. Johnston" 5 => "R. Lang" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1359/jbmr.1998.13.6.1032" "Revista" => array:6 [ "tituloSerie" => "J Bone Miner Res" "fecha" => "1998" "volumen" => "13" "paginaInicial" => "1032" "paginaFinal" => "1038" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9626635" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0195" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A randomized, double-blind comparison of risedronate and etidronate in the treatment of Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "P.D. Miller" 1 => "J.P. Brown" 2 => "E.S. Siris" 3 => "M.S. Hoseyni" 4 => "D.W. Axelrod" 5 => "P.J. Bekker" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Med" "fecha" => "1999" "volumen" => "106" "paginaInicial" => "513" "paginaFinal" => "520" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10335722" "web" => "Medline" ] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0200" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Novel insights into actions of bisphosphonates on bone: differences in interactions with hydrosyapatite" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G.H. Nancollas" 1 => "R. Tang" 2 => "R.J. Phipps" 3 => "Z. Henneman" 4 => "S. Gulde" 5 => "W. Wu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.bone.2005.05.003" "Revista" => array:6 [ "tituloSerie" => "Bone" "fecha" => "2006" "volumen" => "38" "paginaInicial" => "617" "paginaFinal" => "627" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16046206" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0205" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.E. Dunford" 1 => "K. Thompson" 2 => "F.P. Coxon" 3 => "S.P. Luckman" 4 => "F.M. Hahn" 5 => "C.D. Poulter" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Pharmacol Exp Ther" "fecha" => "2001" "volumen" => "296" "paginaInicial" => "235" "paginaFinal" => "242" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11160603" "web" => "Medline" ] ] ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0210" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of a single infusion of zoledronic acid with risedronate for Paget's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "I.R. Reid" 1 => "P. Miller" 2 => "K. Lyles" 3 => "W. Fraser" 4 => "J.P. Brown" 5 => "Y. Saidi" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1056/NEJMoa044241" "Revista" => array:6 [ "tituloSerie" => "N Engl J Med" "fecha" => "2005" "volumen" => "353" "paginaInicial" => "898" "paginaFinal" => "908" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16135834" "web" => "Medline" ] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0215" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of different intravenous bisphosphonate regimens for Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "D. Merlotti" 1 => "L. Gennari" 2 => "G. Martini" 3 => "F. Valleggi" 4 => "V. De Paola" 5 => "A. Avanzati" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1359/jbmr.070704" "Revista" => array:6 [ "tituloSerie" => "J Bone Miner Res" "fecha" => "2007" "volumen" => "22" "paginaInicial" => "1510" "paginaFinal" => "1517" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17605632" "web" => "Medline" ] ] ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0220" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A multicenter trial of low dose of gallium nitrate in patients with advanced Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.S. Bockman" 1 => "F. Wihelm" 2 => "E. Siris" 3 => "F. Singer" 4 => "A. Chausmer" 5 => "R. Bitton" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "1995" "volumen" => "80" "paginaInicial" => "590" "paginaFinal" => "600" ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0225" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dramatic response to plycamicin in a patient with severe Paget's disease refractory to calcitonin and pamidronate" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "S.J. Wimalawansa" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Semin Arthritis Rheum" "fecha" => "1994" "volumen" => "4" "paginaInicial" => "267" "paginaFinal" => "268" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1091977" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S0959289X0090832X" "estado" => "S300" "issn" => "0959289X" ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0230" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Surgical management of Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J. Parvizi" 1 => "G.R. Klein" 2 => "F.H. Sim" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1359/jbmr.06s214" "Revista" => array:7 [ "tituloSerie" => "J Bone Miner Res" "fecha" => "2006" "volumen" => "21" "numero" => "Suppl. 2" "paginaInicial" => "P75" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17229013" "web" => "Medline" ] ] "itemHostRev" => array:3 [ "pii" => "S000293780078224X" "estado" => "S300" "issn" => "00029378" ] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0235" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Discriminative value of biochemical markers of bone turnover in assessing the activity of Paget's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Álvarez" 1 => "N. Guañabens" 2 => "P. Peris" 3 => "A. Monegal" 4 => "J.L. Bedini" 5 => "R. Deulofeu" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/jbmr.5650100318" "Revista" => array:6 [ "tituloSerie" => "J Bone Miner Res" "fecha" => "1995" "volumen" => "10" "paginaInicial" => "458" "paginaFinal" => "465" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7785468" "web" => "Medline" ] ] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0240" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Relationship between biochemical markers of bone turnover and bone scintigraphic indices in assessment of Paget's disease activity" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Álvarez" 1 => "P. Peris" 2 => "F. Pons" 3 => "N. Guañabens" 4 => "R. Herranz" 5 => "A. Monegal" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Arthritis Rheum" "fecha" => "1997" "volumen" => "40" "paginaInicial" => "461" "paginaFinal" => "468" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9082934" "web" => "Medline" ] ] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0245" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of methods of assessing response of Paget's disease to bisphosphonate therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S. Patel" 1 => "C.A.C. Coupland" 2 => "M.D. Stone" 3 => "D.J. Hosking" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Bone" "fecha" => "1995" "volumen" => "16" "paginaInicial" => "193" "paginaFinal" => "197" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7756047" "web" => "Medline" ] ] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0250" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Usefulness of biochemical markers of bone turnover in assessing response to the treatment of Paget's disease" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Álvarez" 1 => "N. Guañabens" 2 => "P. Peris" 3 => "S. Vidal" 4 => "I. Ros" 5 => "A. Monegal" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Bone" "fecha" => "2001" "volumen" => "29" "paginaInicial" => "447" "paginaFinal" => "452" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11704497" "web" => "Medline" ] ] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib0255" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Components of biological variation of biochemical markers of bone turnover in Paget's disease of bone" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "L. Álvarez" 1 => "C. Ricós" 2 => "P. Peris" 3 => "N. Guañabens" 4 => "A. Monegal" 5 => "F. Pons" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Bone" "fecha" => "2000" "volumen" => "26" "paginaInicial" => "571" "paginaFinal" => "576" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10831927" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/21735743/0000000800000004/v1_201305061641/S2173574312000159/v1_201305061641/en/main.assets" "Apartado" => array:4 [ "identificador" => "8450" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Continuing medical educatiion" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735743/0000000800000004/v1_201305061641/S2173574312000159/v1_201305061641/en/main.pdf?idApp=UINPBA00004M&text.app=https://reumatologiaclinica.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173574312000159?idApp=UINPBA00004M" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 21 | 20 | 41 |
| 2024 October | 97 | 83 | 180 |
| 2024 September | 105 | 60 | 165 |
| 2024 August | 109 | 75 | 184 |
| 2024 July | 58 | 71 | 129 |
| 2024 June | 87 | 73 | 160 |
| 2024 May | 70 | 59 | 129 |
| 2024 April | 70 | 50 | 120 |
| 2024 March | 52 | 74 | 126 |
| 2024 February | 54 | 58 | 112 |
| 2024 January | 32 | 34 | 66 |
| 2023 December | 33 | 34 | 67 |
| 2023 November | 42 | 51 | 93 |
| 2023 October | 42 | 49 | 91 |
| 2023 September | 132 | 59 | 191 |
| 2023 August | 37 | 39 | 76 |
| 2023 July | 27 | 41 | 68 |
| 2023 June | 44 | 41 | 85 |
| 2023 May | 37 | 30 | 67 |
| 2023 April | 36 | 18 | 54 |
| 2023 March | 76 | 49 | 125 |
| 2023 February | 72 | 49 | 121 |
| 2023 January | 42 | 30 | 72 |
| 2022 December | 85 | 48 | 133 |
| 2022 November | 101 | 51 | 152 |
| 2022 October | 82 | 54 | 136 |
| 2022 September | 43 | 41 | 84 |
| 2022 August | 49 | 44 | 93 |
| 2022 July | 45 | 39 | 84 |
| 2022 June | 34 | 58 | 92 |
| 2022 May | 46 | 68 | 114 |
| 2022 April | 66 | 56 | 122 |
| 2022 March | 68 | 93 | 161 |
| 2022 February | 78 | 72 | 150 |
| 2022 January | 52 | 44 | 96 |
| 2021 December | 35 | 58 | 93 |
| 2021 November | 60 | 61 | 121 |
| 2021 October | 39 | 55 | 94 |
| 2021 September | 39 | 50 | 89 |
| 2021 August | 42 | 50 | 92 |
| 2021 July | 25 | 48 | 73 |
| 2021 June | 58 | 76 | 134 |
| 2021 May | 57 | 72 | 129 |
| 2021 April | 124 | 175 | 299 |
| 2021 March | 86 | 53 | 139 |
| 2021 February | 66 | 46 | 112 |
| 2021 January | 48 | 50 | 98 |
| 2020 December | 47 | 26 | 73 |
| 2020 November | 47 | 22 | 69 |
| 2020 October | 29 | 15 | 44 |
| 2020 September | 66 | 43 | 109 |
| 2020 August | 24 | 25 | 49 |
| 2020 July | 17 | 27 | 44 |
| 2020 June | 43 | 29 | 72 |
| 2020 May | 32 | 29 | 61 |
| 2020 April | 29 | 16 | 45 |
| 2020 March | 16 | 12 | 28 |
| 2020 February | 2 | 0 | 2 |
| 2020 January | 4 | 0 | 4 |
| 2019 September | 4 | 0 | 4 |
| 2019 June | 1 | 0 | 1 |
| 2019 March | 1 | 0 | 1 |
| 2019 January | 1 | 0 | 1 |
| 2018 June | 1 | 0 | 1 |
| 2018 May | 8 | 2 | 10 |
| 2018 April | 196 | 3 | 199 |
| 2018 March | 119 | 5 | 124 |
| 2018 February | 117 | 7 | 124 |
| 2018 January | 94 | 7 | 101 |
| 2017 December | 98 | 6 | 104 |
| 2017 November | 97 | 11 | 108 |
| 2017 October | 40 | 7 | 47 |
| 2017 September | 43 | 13 | 56 |
| 2017 August | 37 | 11 | 48 |
| 2017 July | 38 | 15 | 53 |
| 2017 June | 74 | 14 | 88 |
| 2017 May | 77 | 12 | 89 |
| 2017 April | 59 | 11 | 70 |
| 2017 March | 60 | 7 | 67 |
| 2017 February | 42 | 10 | 52 |
| 2017 January | 49 | 9 | 58 |
| 2016 December | 88 | 18 | 106 |
| 2016 November | 78 | 23 | 101 |
| 2016 October | 132 | 21 | 153 |
| 2016 September | 89 | 17 | 106 |
| 2016 August | 85 | 9 | 94 |
| 2016 July | 59 | 15 | 74 |
| 2016 June | 1 | 0 | 1 |
| 2016 February | 2 | 0 | 2 |
| 2015 December | 2 | 0 | 2 |
| 2015 November | 1 | 0 | 1 |
| 2015 September | 2 | 0 | 2 |
| 2015 August | 3 | 0 | 3 |
| 2015 July | 31 | 5 | 36 |
| 2015 June | 42 | 11 | 53 |
| 2015 May | 59 | 27 | 86 |
| 2015 April | 59 | 33 | 92 |
| 2015 March | 40 | 19 | 59 |
| 2015 February | 50 | 17 | 67 |
| 2015 January | 70 | 11 | 81 |
| 2014 December | 57 | 16 | 73 |
| 2014 November | 42 | 15 | 57 |
| 2014 October | 56 | 19 | 75 |
| 2014 September | 43 | 16 | 59 |
| 2014 August | 42 | 20 | 62 |
| 2014 July | 48 | 18 | 66 |
| 2014 June | 71 | 13 | 84 |
| 2014 May | 67 | 27 | 94 |
| 2014 April | 51 | 17 | 68 |
| 2014 March | 60 | 29 | 89 |
| 2014 February | 66 | 21 | 87 |
| 2014 January | 55 | 21 | 76 |
| 2013 December | 62 | 20 | 82 |
| 2013 November | 53 | 38 | 91 |
| 2013 October | 63 | 23 | 86 |
| 2013 September | 54 | 16 | 70 |
| 2013 August | 58 | 29 | 87 |
| 2013 July | 51 | 18 | 69 |
| 2013 June | 41 | 28 | 69 |
| 2013 May | 42 | 38 | 80 |
| 2013 April | 52 | 43 | 95 |
| 2013 March | 55 | 39 | 94 |
| 2013 February | 72 | 46 | 118 |
| 2013 January | 30 | 23 | 53 |
| 2012 December | 41 | 25 | 66 |
| 2012 November | 39 | 23 | 62 |
| 2012 October | 24 | 13 | 37 |
| 2012 September | 35 | 9 | 44 |
Show all
