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=> array:2 [ "etiqueta" => "<span class="elsevierStyleSup">l</span>" "identificador" => "aff0060" ] ] ] 7 => array:3 [ "nombre" => "Ariana" "apellidos" => "Alvarado Ceballos" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">i</span>" "identificador" => "aff0045" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">k</span>" "identificador" => "aff0055" ] ] ] 8 => array:3 [ "nombre" => "José Manuel" "apellidos" => "Aguilera Zepeda" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">f</span>" "identificador" => "aff0030" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">k</span>" "identificador" => "aff0055" ] ] ] 9 => array:3 [ "nombre" => "Víctor" "apellidos" => "Mercado Cárdenas" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">g</span>" "identificador" => "aff0035" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">j</span>" "identificador" => "aff0050" ] ] ] 10 => array:3 [ "nombre" => "Hilario" "apellidos" => "Ávila Amengol" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">h</span>" "identificador" => "aff0040" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">j</span>" "identificador" => "aff0050" ] ] ] ] "afiliaciones" => array:12 [ 0 => array:3 [ "entidad" => "Unidad de Epidemiología Clínica, Hospital Infantil de México Federico Gómez-Facultad de Medicina de la Universidad Nacional Autónoma de México, Mexico City, Mexico" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "R A C Salud Consultores, S.A. de C.V., Mexico City, Mexico" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Hospital Regional 1ro de Octubre del ISSSTE, Mexico City, Mexico" "etiqueta" => "d" "identificador" => "aff0020" ] 4 => array:3 [ "entidad" => "Departamento de Investigación y Capacitación, Servicios de Salud de Morelos, Morelos, Mexico" "etiqueta" => "e" "identificador" => "aff0025" ] 5 => array:3 [ "entidad" => "Academia Mexicana de Cirugía, Mexico City, Mexico" "etiqueta" => "f" "identificador" => "aff0030" ] 6 => array:3 [ "entidad" => "Clínica Integral de Menopausia del Centro Médico Dalinde, Mexico City, Mexico" "etiqueta" => "g" "identificador" => "aff0035" ] 7 => array:3 [ "entidad" => "Servicio de Reumatología del Hospital Civil Dr. Juan I. Menchaca, Guadalajara, Mexico" "etiqueta" => "h" "identificador" => "aff0040" ] 8 => array:3 [ "entidad" => "Hospital Angeles Mocel, Mexico City, Mexico" "etiqueta" => "i" "identificador" => "aff0045" ] 9 => array:3 [ "entidad" => "Asociación Mexicana de Metabolismo Óseo y Mineral (AMMOM), Mexico City, Mexico" "etiqueta" => "j" "identificador" => "aff0050" ] 10 => array:3 [ "entidad" => "Colegio Mexicano de Ortopedia y Traumatología, Mexico City, Mexico" "etiqueta" => "k" "identificador" => "aff0055" ] 11 => array:3 [ "entidad" => "Colegio Mexicano de Reumatología, Mexico City, Mexico" "etiqueta" => "l" "identificador" => "aff0060" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Osteoporosis severa: fundamentos para su terapia farmacológica en México" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Osteoporosis (OP) is currently a public health problem due to fracture occurrence and impaired quality of life in patients worldwide.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> The stages include severe or established OP, defined by the World Health Organization as the presence of a previous fracture and a bone densitometry (BMD) 2.5 SD or more below the mean value, measured by DXA.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The prevalence of OP and fractures increases with age: 20% in the population aged 50–59 years; 46% in the population aged 60–69 years; 59% in the population aged 70–79 years and 69% in the population aged >80 years.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> Vertebral and hip fractures have a major influence on mortality rates.<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,6</span></a> Globally, the economic impact of these fractures is significant.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In Mexico, the direct cost of more than 75,000 fragility fractures was estimated at 256.2 million dollars in 2010, and a real growth of 41.7% is expected in this area for 2020.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">There are 2 pharmacological approaches in the treatment of patients with OP aimed at reducing the risk for fracture:<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> anabolic treatment, which stimulates bone formation, and anti-resorptive treatment, which decreases bone resorption.<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10,11</span></a> There are several drug therapy options in the 2016 edition of the Basic Table and the Catalogue of Health Sector Drugs in Mexico (CBCMSS), drawn up by the General Health Council, a constitutional collegiate body and the highest health authority in the country,<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> which include bisphosphonates, calcitriol and calcitonin in the first line. However, in the event of first-line treatment failure or if the patient has severe OP, second line drugs are indicated.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Therapeutic failure is characterized as: 1) presenting 2 or more incident fragility fractures; 2) presenting an incident fracture and high baseline serum levels of β-carboxy-terminal telopeptide of collagen type I (βCTX) or N-terminal propeptide (PINP) of type I without significant reduction during treatment, a significant decrease in BMD or both and 3) presenting non-significant reduction in βCTX or PINP and significant decrease in BMD.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Currently, in Mexico only teriparatide and denosumab are the drugs whose descriptive card in the CBCMSS shows that they are indicated in patients with severe OP or those with therapeutic failure to first-line agents. In the CBCMSS, teriparatide is a hormone with anabolic activity that belongs to group 5 (endocrinology and metabolism) and is indicated for women and men with OP with previous hip or spinal fractures, high risk of refracture and who have not responded to treatment with calcitriol or bisphosphonates. Denosumab is a monoclonal antibody that also belongs to group 5, and group 17 (oncology) as well, and is indicated in postmenopausal women who are intolerant to oral bisphosphonates, with previous fracture or with a high risk for fracture.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The present paper, therefore, will focus exclusively on these 2 drugs.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The objective of this article was to perform a systematic and narrative review of the evidence on these drugs, as well as a pharmacological comparison of efficacy, effectiveness, and safety between teriparatide and denosumab and to analyse the recommendations established for severe OP in national and international treatment guidelines. This document includes the position of 3 societies in this regard: The Bone and Mineral Metabolism Association, the Mexican College of Orthopaedics and Traumatology and the Mexican College of Rheumatology.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0030" class="elsevierStylePara elsevierViewall">For the pharmacological review of the drugs, the differences in the mechanisms of action, pharmacokinetics, pharmacodynamics and safety and tolerability profile a specialist review was undertaken in 2 platforms, Micromedex®, Truven Health Analytics,<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> and the VigiBase®,<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> platform, which is the World Health Organization's global database for reporting adverse reactions for both drugs.</p><p id="par0035" class="elsevierStylePara elsevierViewall">For the analysis of effectiveness, efficacy and safety, a systematic review of the literature was conducted, focusing on a search for randomised clinical trials of both drugs, compared with placebo or another molecule using the following terms: <span class="elsevierStyleItalic">Severe osteoporosis/established osteoporosis (teriparatide/denosumab); Severe osteoporosis denosumab or teriparatide; Severe osteoporosis and teriparatide or denosumab</span>, in the following: PubMed, Cochrane Library and TripDatabase (until 2017). Two investigators undertook screening by title, abstract and full text in parallel and independently, and discrepancies were resolved with the intervention of a third investigator.</p><p id="par0040" class="elsevierStylePara elsevierViewall">The inclusion criteria were in accordance with the acronym PICO. Population: adult females diagnosed with OP receiving drug treatment. Interventions: teriparatide or denosumab, under their approved dosage and application regimens. Comparators: compared with placebo. Measurement of fracture outcomes (by anatomical site) and adverse events leading to discontinuation of the study. The methodological quality was evaluated by applying the criteria of the Spanish version of the Critical Appraisals Skills Programme (CASPe).<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Finally, the clinical practice guidelines and national consensuses: CENETEC 2013,<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> AMMOM 2015,<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Interdisciplinary Groups 2015<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> and CENAPRECE 2017,<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> and international institutions such as ESCEO/IOF Europe 2013,<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> NOGG UK 2017,<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> NICE updated 2010 and 2017,<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Haute Autorité de Santé France 2014,<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> AACE/ACE USA 2016<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> were considered for analysis of the recommendations on therapy for severe OP.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Results</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Pharmacological comparison</span><p id="par0050" class="elsevierStylePara elsevierViewall">Teriparatide is a synthetic polypeptide hormone made up of the first 34 amino acids of human parathyroid hormone (PTH),<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> which give it its biological activity, <a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> mimicking the actions of endogenous PTH, resulting in a catabolic effect on bone. However, when administered in low doses and intermittently, it results in anabolic properties in the bone system.<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27–30</span></a> Administered by subcutaneous injection of 20 μg once a day, serum concentrations peak at 30 min and decrease to undetectable levels after 3 h. The bioavailability of teriparatide is 95% on average, with a one-hour half-life, with elimination of 62 L/h in women and 94 L/h in men. Elimination occurs by non-specific enzymatic mechanisms in the liver, followed by its excretion via the kidneys (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Denosumab is a human monoclonal antibody of recombinant DNA origin that binds to the cytosine RANKL (receptor activator of nuclear factor k B ligand), which prevents its binding to the RANK osteoclast membrane receptors (NFB receptor activator of NFκB). By reducing RANKL-RANK binding, the formation of the mature osteoclast is inhibited thus promoting decreased bone resorption.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">31–33</span></a> With these characteristics, the effect of osteoprotegerin, which is fundamental for bone resorption capacity, is simulated.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> After a subcutaneous dose of 60 mg, bioavailability is 61%, maximum serum concentration (C<span class="elsevierStyleInf">max</span>) is 6 μg/mL (range 1–17 μg/mL) in an average of 10 days (range 2–28 days), with a half-life of 26 days (range 6–52 days) (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Main pharmacological differences between teriparatide and denosumab</span><p id="par0060" class="elsevierStylePara elsevierViewall">There are significant differences between the two agents at all levels of classification according to the Anatomical, Therapeutic, Chemical (ATC) Classification System.<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> With pharmacokinetic and pharmacodynamic properties that differ radically from each other in terms of pharmacophore, biological, mechanistic, and chemical activity (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>).</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Safety and tolerability profile</span><p id="par0065" class="elsevierStylePara elsevierViewall">Safety can be determined by the frequency and severity of adverse reactions. In the case of denosumab, adverse events reported for the therapeutic indications for this drug are included, not only OP studies. The most frequent adverse reactions to denosumab include constipation, sciatica, exanthem rashes, limb pain, cataracts, among others. Mention should be made of mandibular osteonecrosis (1%–2%) and associated atypical fractures (case series report), serious events that warrant discontinuation of treatment.<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37–39</span></a> The most frequent adverse reactions to teriparatide include nausea, limb pain, dizziness and hyperuricaemia.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25,35</span></a> Specialist consultation in Micromedex,<span class="elsevierStyleItalic">®</span> finds differences and similarities in the safety and tolerability of each of these drugs (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>).<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> When assessing adverse reactions reported in VigiBase<span class="elsevierStyleItalic">®</span> up until May 2017, 95,175 adverse reaction reports were made over the last 27 years for teriparatide, and 50,680 for denosumab over a period of 14 years.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Efficacy and safety reported in clinical trials</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results from the selection</span><p id="par0070" class="elsevierStylePara elsevierViewall">From the electronic libraries consulted, analysing a total of 411 original references, 2 studies were obtained (kappa .40–.80; <span class="elsevierStyleItalic">P</span> < .0001), both of high methodological quality (10 of 11 CASPe items).</p><p id="par0075" class="elsevierStylePara elsevierViewall">The 2 clinical trials selected are pivotal studies of teriparatide<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> and denosumab<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a>: it should be noted that the proportion of patients with prevalent vertebral fracture varied significantly between these studies. The teriparatide study<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> included patients with at least one moderate fracture or 2 mild fractures not caused by trauma to the vertebrae,<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> while the study of denosumab only included 24% of patients with this characteristic.<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37,40</span></a> Another important difference was that 15%–16% of the patients in the teriparatide study had received previous therapy for unspecified OP,<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> but not in the denosumab study. However, the remaining baseline characteristics such as age, sex, body mass index and T score at the lumbar spine were comparable<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>).</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0080" class="elsevierStylePara elsevierViewall">The primary measure of efficacy in both studies was a statistically significant reduction in the occurrence of vertebral fragility refracture (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). Comparison against placebo showed an RR of .35 (95% CI: .22−.55) for teriparatide and .32 (95% CI: .26−.41) for denosumab. The absolute risk reduction (ARR) was higher with teriparatide than with denosumab (9.3% vs 4.8%), although the follow-up time was shorter in the teriparatide study (21 months) than in the denosumab study (36 months).<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29,40</span></a></p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">Occurrence of non-vertebral fragility fractures was a secondary measure of efficacy in both studies (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29,40</span></a> In both cases a significant reduction in their incidence was achieved, although the point estimate varied significantly: RR .47 (95% CI: .25−.88) with teriparatide and HR .80 (95% CI: .67–.96) with denosumab. This implies that teriparatide reduced the incidence of non-vertebral fragility fractures by 53%, while the reduction obtained with denosumab was 20%. The ARR was also higher with teriparatide than with denosumab (2.9% vs. 1.5%). Another difference to consider is that the risk estimates in the denosumab study come from a Kaplan-Meier analysis,<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> while those corresponding to teriparatide are simple proportions.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Denosumab showed a reduction in the risk for fragility hip fracture of HR .60 (95% CI .37–.97). The teriparatide study indicates that the number of non-vertebral fragility fracture events, not anatomical site-specific, was too low to precisely estimate their incidence, and that the point estimate of RR for hip fracture compared to placebo was .25, which represents a reduction of 75%.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The two studies categorised adverse events differently, although they had in common the classification of adverse events leading to discontinuation of therapy, shown in <a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>. As can be seen, the point incidences are similar between both agents and in neither of the 2 cases were the differences statistically significant.</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Narrative review of recommendations in clinical practice guidelines and consensuses</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">National guidelines</span><p id="par0095" class="elsevierStylePara elsevierViewall">The 4 guidelines consulted clearly distinguish the mechanisms of action of both agents, defining teriparatide as osteoforming and denosumab as anti-resorptive. They all emphasize that teriparatide should be administered in high-risk populations, such as women with OP and those with previous fractures, i.e., with severe OP. For denosumab, the recommendation is that it should be used in women who are not candidates for first-line drugs. All recommendations agree on the need for subsequent treatment after discontinuation of teriparatide or denosumab (<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>).</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">International guidelines</span><p id="par0100" class="elsevierStylePara elsevierViewall">The main guidelines identified at international level (North America, Europe, South America and Australia<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">21–24,41–45</span></a>) refer to the difference of both drugs in terms of their mechanisms of action and treatment approach (osteoforming and anti-resorptive). The guidelines consulted recommend teriparatide in patients at high or extremely high risk for fracture, either as first or second line, after failure with anti-resorptive agents or in some cases if there is intolerance. Denosumab is recommended as a first-line alternative in high-risk patients and as agent of choice in patients with renal failure. Most of the authors agree in recommending its use in case of intolerance or contraindication to bisphosphonates (<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>).</p></span></span></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discussion and conclusions</span><p id="par0105" class="elsevierStylePara elsevierViewall">The present document summarises the 2 pharmacological treatment approaches for severe OP: teriparatide anabolic (osteoforming) and denosumab catabolic (anti-resorptive). It also summarises the specific indications for their administration in accordance with the CBCMSS descriptive cards, adverse events according to the Micromedex® and VigiBase® platforms and, finally, it summarises the therapeutic indications published in the different national and international guidelines for this entity.</p><p id="par0110" class="elsevierStylePara elsevierViewall">Teriparatide, a synthetic polypeptide hormone, directly stimulates osteoblasts to form new bone; while denosumab, a monoclonal antibody, inhibits osteoclastogenesis. The anti-fracture efficacy of both drugs has been sufficiently proven, but due to their different mechanisms of action, therapeutic interchange or therapeutic substitution are not indicated. The criteria for therapeutic substitution do not apply in the case of 2 drugs belonging to different ATC classes and therefore differing in their pharmacological composition, which can lead to heterogeneous efficacy and safety profiles that are not very comparable.</p><p id="par0115" class="elsevierStylePara elsevierViewall">On the other hand, results of indirect comparisons and network meta-analyses involving pivotal clinical trials of teriparatide and denosumab should be viewed cautiously due to differences in some baseline characteristics of the patients recruited, which are critical (e.g., percentage of women with previous fracture).<a class="elsevierStyleCrossRefs" href="#bib0230"><span class="elsevierStyleSup">46,47</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Teriparatide is indicated in men and women with severe OP, high risk for refracture, risk for imminent fracture or those who have not responded to treatment with calcitriol or bisphosphonates. Denosumab is indicated for postmenopausal women who are intolerant to bisphosphonates, women with previous fracture and risk of subsequent fractures and for the prevention of bone complications (pathological fractures, bone radiotherapy, spinal cord compression or bone surgery), in patients with breast cancer with bone metastasis and with signs of impaired renal function.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">It is important to note that there is inter-institutional agreement on the criteria and main recommendations issued by national and international clinical practice guidelines. However, there are no data for us to determine the level that physicians adhere to the cards when prescribing.</p><p id="par0130" class="elsevierStylePara elsevierViewall">Both drugs have an acceptable safety profile, as the most frequent adverse reactions are mild and moderate and do not put the patient's life at risk. Although the number of reports of suspected adverse reactions is approximately double for teriparatide (95,175 in 27 years) compared to denosumab (50,680 in 14 years). This could be attributed to the difference in years on the market, together with the emphasis on adverse reaction reporting, especially with innovative products, over the last decade. Finally, we must bear in mind that there are drugs with more adverse reactions per se.</p><p id="par0135" class="elsevierStylePara elsevierViewall">The recommendations issued in national and international guidelines follow a general pattern in terms of the indication of both drugs for treating severe OP in patients with inadequate response to bisphosphonates. However, they cannot be said to be substitutable for the reasons mentioned above. Therefore, their prescription should be individualised and based on the characteristics of the patient, such as age, site of previous fractures, risk profile, previous treatments, and desired effect, to achieve better clinical outcomes.</p><p id="par0140" class="elsevierStylePara elsevierViewall">It is important to highlight that recent research on the sequence of OP treatment in patients with imminent risk for fracture, understood as imminent risk the first year following a vertebral or hip fracture,<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> has shown that the use of teriparatide is recommended primarily to build bone mass, followed by transition to denosumab or a bisphosphonate, considering the benefit in BMD gain with this sequence.<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49,50</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">One of the strengths of the present study which means we can take a position on the treatment of severe OP is our use of solid literature search methodologies and having consulted reliable databases, and the involvement of specialist researchers in various areas of knowledge, which enabled a comprehensive and multidisciplinary approach.</p><p id="par0150" class="elsevierStylePara elsevierViewall">Given the nature of the summary studies, the main limitation of this work is the inclusion of studies with highly heterogeneous population characteristics. This shortcoming is attributed to the availability of primary studies.</p><p id="par0155" class="elsevierStylePara elsevierViewall">The position of this working group based on the published evidence can be summarised as follows: a) both medicines have high quality evidence according to CASPe and are indicated in the treatment of severe or established OP, b) teriparatide and denosumab belong to different therapeutic classes, with biologically opposed mechanisms of action and clearly differentiated indications for use on their respective CBCMSS descriptive cards, and therefore, c) these medicines are not interchangeable or substitutable in the treatment of severe OP.</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Funding</span><p id="par0160" class="elsevierStylePara elsevierViewall">This project was undertaken with an unrestricted grant, number <span class="elsevierStyleGrantNumber" refid="gs0005">4100501768</span> from <span class="elsevierStyleGrantSponsor" id="gs0005">Eli Lilly & Compañía de México</span>, S.A. de C.V. in which the authors had full autonomy in its development.</p><p id="par0165" class="elsevierStylePara elsevierViewall">This study was carried out by a multidisciplinary group of experts in systematic review methodology and a group of experts in the field. This review was endorsed by the Mexican College of Rheumatology, the Mexican College of Orthopaedics and the Mexican Association of Bone and Mineral Metabolism.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflict of interests</span><p id="par0170" class="elsevierStylePara elsevierViewall">The authors have no conflict of interests to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres1457079" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1328188" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1457080" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1328187" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Methods" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Results" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Pharmacological comparison" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Main pharmacological differences between teriparatide and denosumab" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Safety and tolerability profile" ] 3 => array:3 [ "identificador" => "sec0035" "titulo" => "Efficacy and safety reported in clinical trials" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Results from the selection" ] ] ] 4 => array:3 [ "identificador" => "sec0045" "titulo" => "Narrative review of recommendations in clinical practice guidelines and consensuses" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "National guidelines" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "International guidelines" ] ] ] ] ] 7 => array:2 [ "identificador" => "sec0060" "titulo" => "Discussion and conclusions" ] 8 => array:2 [ "identificador" => "sec0065" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0070" "titulo" => "Conflict of interests" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-01-04" "fechaAceptado" => "2019-04-04" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1328188" "palabras" => array:5 [ 0 => "Osteoporotic fractures" 1 => "Teriparatide" 2 => "Denosumab" 3 => "Mexico" 4 => "Severe osteoporosis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1328187" "palabras" => array:5 [ 0 => "Fracturas osteoporóticas" 1 => "Teriparatida" 2 => "Denosumab" 3 => "México" 4 => "Osteoporosis severa" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">This article presents evidence and recommendations regarding the efficacy and safety of the approved and available therapies in Mexico to treat severe or established osteoporosis (OP) with the aim of developing a position regarding therapeutics in this stage of the disease, according to the descriptive cards of the National Drug Formulary of the National General Health Council of Mexico (CBCMSS).</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">We performed a systematic and narrative review of the evidence of teriparatide and denosumab, from their pharmacological profile, effectiveness, and safety derived from clinical trials, as well as an analysis of the general recommendations of the national and international clinical practice guidelines.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">The evidence establishes that teriparatide and denosumab belong to different therapeutic classes, with biologically opposed mechanisms of action and indications of use, which are clearly differentiated in their respective national codes, therefore these drugs cannot be substitutable or interchangeable in severe OP therapy. Both represent the best options currently available for this stage of the disease; being similar in their efficacy in preventing new vertebral fragility fractures, with an RR of .35 (CI = 95%, .22−.55) for teriparatide, and .32 (CI = 95%, .26−.41) for denosumab. The absolute risk reduction (RRR) is higher with teriparatide 9.3% (21 months) compared with denosumab at 4.8% (36 months).</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Our results agree with the recommendations available in national and international clinical practice guidelines, with both therapies proposed as a sequential, but not a substitute, treatment.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes</span><p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">El presente artículo muestra la evidencia y recomendaciones al respecto de la eficacia y seguridad de las terapias hasta hoy aprobadas y disponibles en México para el tratamiento de la osteoporosis (OP) en su etapa severa o establecida, con la finalidad de establecer una postura terapéutica acerca de la eficacia y seguridad para esta etapa del padecimiento, de acuerdo a las cédulas descriptivas del Cuadro Básico y Catálogo de Medicamentos del Sector Salud en México (CBCMSS).</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Métodos</span><p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Se realizó una revisión sistemática y narrativa de la evidencia de teriparatida y denosumab, desde su perfil farmacológico, efectividad y seguridad derivada de ensayos clínicos, además de un análisis de las recomendaciones generales de las principales guías de práctica clínica nacionales e internacionales.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">La evidencia establece que teriparatida y denosumab pertenecen a clases terapéuticas distintas, con mecanismos de acción biológicamente opuestos e indicaciones de uso claramente diferenciadas en sus respectivas cédulas, por lo cual no son sustituibles o intercambiables en la terapia de OP severa. Ambas representan la mejor opción disponible hasta el momento para esta etapa del padecimiento; siendo similares en su eficacia de prevención de nuevas fracturas vertebrales por fragilidad, con un RR de 0,35 (IC = 95%, 0,22−0,55) para teriparatida, y de 0;32 (IC = 95%, 0,26–0,41) para denosumab. La reducción absoluta del riesgo (RRR) es mayor con teriparatida 9,3% (21 meses) en comparación con denosumab 4,8% (36 meses).</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">Nuestros resultados concuerdan con las recomendaciones disponibles en las principales guías de práctica clínica nacionales e internacionales, siendo propuestas ambas terapias como consecutivas y nunca sustitutivas.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0025">Please cite this article as: Clark P, Rivera FC, Méndez Sánchez L, Mendoza Gutiérrez CF, Vargas Neri JL, Carrillo Vázquez SM, et al. Osteoporosis severa: fundamentos para su terapia farmacológica en México. Reumatol Clin. 2021;17:97–105.</p>" ] ] "multimedia" => array:8 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Table " "rol" => "short" ] ] "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"><th 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" scope="col" style="border-bottom: 2px solid black">Pharmacology \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Teriparatide \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Denosumab \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ATC Code \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">H05AA02 - Teriparatide \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">M05BX04 - Denosumab \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">H-Systemic Hormone Preparations \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">M-Musculo-skeletal system \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">H05-Calcium homeostasis \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">M05-Drugs used for the treatment of bone diseases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">H05A-Parathyroid hormones and analogues \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">M05B-Drugs affecting bone structure and mineralisation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">H05AA-Parathyroid Hormones and analogues \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">MB05BX-Other drugs affecting bone structure and mineralization \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Structure \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"><elsevierMultimedia ident="202101301157398641"></elsevierMultimedia> \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"><elsevierMultimedia ident="202101301157398642"></elsevierMultimedia> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">Polypeptide chain \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">Monoclonal antibody \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Molecular weight \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">4,117.7 Daltons \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">144,700.0 Daltons \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Description \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">Synthetic polypeptide hormone comprised of amino acids 1–34 of the human parathyroid hormone (HPT). It is the biologically active N-terminal region of PTH \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">Fully human IgG2 monoclonal antibody specific to RANKL (nuclear factor kappa-B ligand) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dose \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">20 μg once a day up to 18 months \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">60 mg once every 6 months \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Route \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">Subcutaneous \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">Subcutaneous \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 " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pharmacodynamics</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mechanism of action \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">Mimics the mechanism of action of PTH, stimulating bone formation by direct effect on osteoblasts and on intestinal absorption of calcium \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">Specifically binds to RANKL, inhibits the formation of RANKL-RANK complex, and indirectly causes a decrease in the formation and activity of osteoclasts \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 " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pharmacokinetics</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Absorption</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bioavailability (subcutaneous administration) \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">95% \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">61% \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Maximum plasma concentration (Cmax) \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">Approximately 140 pg/mL \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">6 μg/mL (range from 1–17 μg/mL) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Time to Cmax (Tmax) \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">20−30 min \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">10 days (range from 2 to 28 days) \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 " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Distribution</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Binding to proteins \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">Yes. It is assumed that it is transported in the same way as parathyroid hormone (PTH), through the alpha-globulin fraction \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">Not available, although it is considered that behaviour is the same as other monoclonal antibodies which do not bind to proteins \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Volume of distribution (Vd) \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">1 L/kg (intravenous) \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">No values are indicated; however, it has been mentioned that extravascular distribution decreases \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 " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Metabolism</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Site of metabolism \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">Hepatic \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">Metabolism could be mediated by 3 mechanisms: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">It is assumed that it is metabolised in the same way as PTH, through proteolytic liver enzymes \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">a) Proteolysis by the liver and by the reticuloendothelial system \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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"> \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">b) Elimination mediated by markers \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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"> \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">c) Non-specific endocytosis followed by intracellular degradation. In this type of mechanism there can be protection of the Fc portion, causing increased half-life time \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 " colspan="3" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Excretion</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Renal clearance \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">90% \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">Due to its molecular weight, denosumab is not excreted in the urine, it is metabolised to peptides and amino acids, which can be reused for de novo protein synthesis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \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">Renal clearance like that of PTH is assumed \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"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Total clearance \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">Women: 62 L/h Men: 94 L/h \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">Not available \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab2506381.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Main pharmacological differences between teriparatide and denosumab.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Source: Based on information from Micromedex®.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>.</p>" "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"><th 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" scope="col" style="border-bottom: 2px solid black">Teriparatide \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th 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" scope="col" style="border-bottom: 2px solid black">Denosumab \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"><span class="elsevierStyleBold">Cardiovascular effects:</span> angina pectoris (2.5%), hypertension (7.1%), hypotension (case report) and orthostatic hypotension (5%) \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"><span class="elsevierStyleBold">Cardiovascular effects:</span> angina pectoris (2.6%), endocarditis (case report), hypertension (6.4%), peripheral oedema (24% in hypercalcaemia of malignancy and 4.9% in osteoporosis) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n