Recommendations on the effect of antidiabetic drugs in bone | Endocrinología, Diabetes y Nutrición (English ed.)

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[ "titulo" => "Recomendaciones sobre el efecto de los fármacos antidiabéticos en el hueso" ] ] "textoCompleto" => "IntroductionPatients with diabetes have an increased risk of fracture, and it is therefore important to understand the effect of antidiabetic drugs on bone. Recommendations were made based on the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to establish the strength of recommendations and the level of evidence. A distinction is made between strong recommendations, expressed as “We recommend” and number 1, and weak recommendations, expressed as “We suggest” and number 2. The quality of evidence is expressed using symbols: ØOOO indicates very low evidence; ØØOO low evidence; ØØØO moderate evidence; and ØØØØ high evidence.MetforminRecommendations<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">-We suggest use of metformin as first choice drug to treat T2DM in patients with osteoporosis (2ØØOO). Treatment with metformin causes a slightly increase in bone mineral density (BMD) (2ØØOO), and its effect on risk of fracture is neutral or beneficial (2ØØOO).</li></ul>EvidenceFew studies are available on the effects of metformin in humans. Observational data show a protective effect on risk of fracture, with a hazard ratio (HR) of 0.7 (95% confidence interval [CI]: 95%: 0.6–0.96)<a class="elsevierStyleCrossRef" href="#bib0215">1</a> and an odds ratio (OR) of 0.8 (95% CI: 0.7–0.93).<a class="elsevierStyleCrossRef" href="#bib0220">2</a> In the A Diabetes Outcome Progression Trial (ADOPT), there were no beneficial effects of metformin on risk of fracture at 4 years of follow-up, although levels of formation and resorption markers decreased at 12 months of treatment start.<a class="elsevierStyleCrossRefs" href="#bib0225">3,4</a> As regards the effect of metformin on BMD, the Borges et al. study<a class="elsevierStyleCrossRef" href="#bib0235">5</a> found a slight increase in BMD in the lumbar spine, total hip, and distal third of radius in patients treated with metformin for 80 weeks.GlitazonesRecommendations<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010">-We recommend that use of glitazones is avoided in women with diabetes and osteoporosis or with high fracture risk (1ØØØO). If used, we recommend that such use is considered as a major risk factor for osteoporosis when risk of osteoporotic fracture is assessed (1ØØØO).</li><li class="elsevierStyleListItem" id="lsti0015">-We recommend consideration that glitazones cause variable changes in remodeling markers (BRM) (1ØØØO) and decreases in lumbar, femoral and appendicular BMD (1ØØØO), and double the risk of osteoporotic fractures, especially in menopausal women (1ØØØO).</li></ul>EvidenceData about the effect of rosiglitazone on BMD are conflicting (reviewed in Lecka-Czernik<a class="elsevierStyleCrossRef" href="#bib0240">6</a>), and a recent meta-analysis of 18 trials did not show a consistent pattern in BRM changes.<a class="elsevierStyleCrossRef" href="#bib0245">7</a> Glitazones decrease BMD in lumbar spine (difference −1.1%; 95% CI: −1.6 to −0.7), total hip (−1.0%; 95% CI: −1.4 to −0.6), and forearm (−0.9%; 95% CI: −1.6 to −0.3). Changes in BMD persist one year after treatment discontinuation.<a class="elsevierStyleCrossRef" href="#bib0245">7</a> As regards risk of fracture, observational studies have shown increases (pioglitazone: OR 2.59; 95% CI: 0.96–7.01, and rosiglitazone: OR 2.38; 95% CI: 1.39–4.09) related to age (greater in subjects from 65 years of age) and to longer treatment duration. The risk is higher in females and in subjects with prior fractures. An increased risk has also been reported in males (observational studies, reviewed in Lecka-Czernik<a class="elsevierStyleCrossRef" href="#bib0240">6</a>). By contrast, in a case-control study conducted in an Asian population, glitazones were associated to an increased risk of fracture, especially in women under 64 years of age (OR 1.74–2.58).<a class="elsevierStyleCrossRef" href="#bib0250">8</a> In the ADOPT study<a class="elsevierStyleCrossRef" href="#bib0225">3</a>, rosiglitazone monotherapy was associated to a higher fracture rate (9.30% in 5 years) as compared to metformin (5.08%) and glibenclamide (3.47%) (RR 1.81 and 2.13 respectively). Pioglitazone also increases fracture risk in women (1.9 versus 1.1 fractures per 100 patient-years) (reviewed in Lecka-Czernik<a class="elsevierStyleCrossRef" href="#bib0240">6</a> and McCulloc<a class="elsevierStyleCrossRef" href="#bib0255">9</a>). In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study,<a class="elsevierStyleCrossRef" href="#bib0260">10</a> use of glitazones (74% rosiglitazone, 13% pioglitazone) increased the fracture rate in women only from one year of use (HR ≥2), and risk decreased from one year after drug discontinuation. A meta-analysis<a class="elsevierStyleCrossRef" href="#bib0265">11</a> of controlled studies (13,715 participants) and observational studies (31,679 participants) confirmed that glitazones double the risk of fracture, but only in females.SulfonylureasRecommendations<ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0020">-We suggest that treatment with sulfonylureas may increase risk of hip fracture in patients over 65 years of age and in subjects with documented hypoglycemia (2ØØOO), and also the incidence of falls in institutionalized patients (2ØØOO).</li></ul>EvidenceA prospective, randomized study reported an increase in BMD related to use of sulfonylureas (SU), mediated by increased endogenous C-peptide and proinsulin levels.<a class="elsevierStyleCrossRef" href="#bib0270">12</a> On the other hand, a higher risk of hypoglycemia may increase falls and risk of fracture. In a case-control study, authors reported a lower risk of hip fracture in patients treated with SU.<a class="elsevierStyleCrossRef" href="#bib0220">2</a> In another case-control study with less cases, there was no association between treatment with SU and risk of fracture (OR 0.77; 95% CI: 0.44–1.37).<a class="elsevierStyleCrossRef" href="#bib0275">13</a> Analysis of the risk of vertebral fracture showed that treatment with SU was a protective factor in females but not in males.<a class="elsevierStyleCrossRef" href="#bib0275">13</a>A systematic review conducted in 2013 concluded that no adequate evidence is available to state that a relationship exists between use of SU and risk of fracture.<a class="elsevierStyleCrossRef" href="#bib0280">14</a> However, in a subsequent observational study in patients with diabetes older than 65 years, use of SU was associated to greater risk of hip fracture (OR 1.46; 95% CI: 1.17–1.82) both in females and males. Risk of hip fracture is higher in patients with documented hypoglycemia (OR 2.42; 95% CI: 1.35–4.34).<a class="elsevierStyleCrossRef" href="#bib0285">15</a> In institutionalized patients, start of treatment with SU was not associated to greater risk of fracture, but was related to higher risk of fall (HR 1.13; 95% CI: 1.00–1.26).<a class="elsevierStyleCrossRef" href="#bib0290">16</a>GLP-1 receptor agonists (GLP-1 RAs) and DPP-4 inhibitorsRecommendations<ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0025">-We think that use of DPP-4 inhibitors does not modify risk of fracture (1ØØØO).</li><li class="elsevierStyleListItem" id="lsti0030">-We think that treatment with GLP-1 RAs (exenatide, liraglutide) does not affect BMD (1ØØOO) or risk of fracture (1ØØØO).</li></ul>EvidenceIn the study Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)–Thrombolysis in Myocardial Infarction (TIMI), there were no differences in risk of fracture between saxagliptin and placebo.<a class="elsevierStyleCrossRef" href="#bib0295">17</a> These results were confirmed by a cohort study,<a class="elsevierStyleCrossRef" href="#bib0300">18</a> conducted from 2007 to 2012, which found no differences in risk of fracture between patients treated with DPP-4 inhibitors and controls (adjusted HR 0.89; 95% CI: 0.71–1.13). Treatment with DPP-4 inhibitors did not increase the risk as compared to other non-insulin antidiabetic therapies (HR 1.03; 95% CI: 0.92–1.15). However, as admitted by the authors, treatment duration may have been too short to determine the effect.<a class="elsevierStyleCrossRef" href="#bib0300">18</a> These results are in contrast with those of a meta-analysis of clinical trials<a class="elsevierStyleCrossRef" href="#bib0305">19</a> that showed a 40% decrease in fracture risk in users of DPP-4 inhibitors as compared to active treatment or placebo. Identification of fractures as adverse effects rather than as the primary objective, the low number of fractures seen, and use of different comparators may have influenced the results. In a population study<a class="elsevierStyleCrossRef" href="#bib0310">20</a> of patients with T2DM (mean age, 52 years), use of sitagliptin was not related to higher risk of fracture, while a greater risk was seen in patients treated with sulfonylureas or insulin.In 66 patients with T2DM treated with metformin, treatment with exenatide (n=33) or insulin glargine (n=33) for 44 weeks did not affect BMD, BRMs, or calciotropic hormones.<a class="elsevierStyleCrossRef" href="#bib0315">21</a> A subanalysis of 61 patients from the LEAD 3 study,<a class="elsevierStyleCrossRef" href="#bib0320">22</a> there were no significant changes from baseline in the BMD of patients given liraglutide or glimepiride after 104 weeks of treatment.Different meta-analyses<a class="elsevierStyleCrossRefs" href="#bib0325">23,24</a> and cohort studies have confirmed that treatment with GLP-1 RAs does not affect fracture risk. In a cohort study,<a class="elsevierStyleCrossRef" href="#bib0335">25</a> a lower risk of fracture was not seen in patients treated with GLP-1 RAs as compared to those who had never received them (adjusted HR 0.97; 95% CI: 0.72–1.32). No relationship was also seen between risk of failure and cumulative dose. These findings were confirmed in another case-control study<a class="elsevierStyleCrossRef" href="#bib0340">26</a> where treatment with GLP-1 RAs was not associated to a decreased risk of fracture (OR 1.16; 95% CI: 0.83–1.63). No relationship was also seen between current treatment with GLP-1 RAs and risk of osteoporotic fracture (OR 0.78; 95% CI: 0.44–1.39).In the meta-analysis by Su et al.,<a class="elsevierStyleCrossRef" href="#bib0330">24</a> treatment with liraglutide was associated to a decrease in the risk of incident fractures (Mantel-Haenszel OR 0.38; 95% CI: 0.17–0.87), while exenatide was associated to an increased risk of incident fractures (Mantel-Haenszel OR 2.09; 95% CI: 1.03–4.21). According to the authors, the greater homology of liraglutide with human GLP-1, as well as a longer half-life, could explain the different effects on risk of fracture. However, the low number of fractures reported and the short duration of the studies limit the strength of conclusions.SGLT2 inhibitorsRecommendations<ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0035">-We recommend consideration of the fact that use of canagliflozin is associated to increases in BRMs and to a slight decrease of BMD in total hip (1ØØOO).</li><li class="elsevierStyleListItem" id="lsti0040">-We suggest that treatment with empagliflozin may increase urinary bone resorption markers with no significant increase in number of fractures (2ØØOO).</li><li class="elsevierStyleListItem" id="lsti0045">-We suggest caution when dapagliflozin and canagliflozin are used in some groups of patients, because they may increase risk of fracture (2ØØOO).</li></ul>EvidenceUse of canagliflozin and dapagliflozin has been related to a mild increase in phosphate, magnesium, and iPTH levels, with no significant changes in serum calcium levels and a slight decrease in 1,25-dihydroxyvitamin D levels.<a class="elsevierStyleCrossRef" href="#bib0345">27</a> In a randomized, double-blind study,<a class="elsevierStyleCrossRef" href="#bib0350">28</a> treatment with canagliflozin was associated to decreased serum estradiol levels, a significant increase in BRMs at 52 weeks of treatment, and a decrease in total hip BMD (−0.9% and −1.2% for canagliflozin 100mg and 300mg respectively). Changes seen in BRMs and BMD are partly explained by the weight loss seen. No significant changes were found in the bone resistance parameters tested.<a class="elsevierStyleCrossRef" href="#bib0350">28</a> Treatment with dapagliflozin has not been associated to significant changes in BRMs, 25-hydroxyvitamin A (25OHD) or BMD in the different regions analzed.<a class="elsevierStyleCrossRef" href="#bib0355">29</a> No significant changes have been reported in serum calcium, phosphorus, 25OHD, iPTH or alkaline phosphatase with empagliflozin, but the 25mg dose did slightly but significantly increase urinary levels of amino-terminal collagen crosslinks (NTX).<a class="elsevierStyleCrossRef" href="#bib0360">30</a> As regards BMD, use of empagliflozin does not appear to be associated to clinically significant changes based on the results of a substudy of the comparative clinical trial with glimepiride.<a class="elsevierStyleCrossRef" href="#bib0360">30</a>With regard to fractures, the risk may be increase in some patient subgroups, but limited data are available. Phase IIb/III studies with dapagliflozin have not shown a significant increase in fracture risk.<a class="elsevierStyleCrossRef" href="#bib0365">31</a> However, among patients with moderate kidney failure, 9.4% and 6% of those treated with dapagliflozin 10mg and 5mg respectively sustained a fracture during treatment at 104 weeks, while subjects given placebo sustained no fractures. After excluding fractures in not typically osteoporotic locations, 7% of patients on dapagliflozin 10mg sustained fractures.<a class="elsevierStyleCrossRef" href="#bib0370">32</a> In a recent meta-analysis of nine clinical trials, use canagliflozina was related to an increased incidence of fractures, mainly in subjects participating in the Canagliflozin Cardiovascular Assessment Study (CANVAS) (4% canagliflozin vs 2.6% placebo), representing an older population with high cardiovascular risk.<a class="elsevierStyleCrossRef" href="#bib0375">33</a> Mean drug exposure was 85 weeks, and although the risk appears in the first weeks of treatment, it seems to continue over time. Finally, the results of the EMPA-REG OUTCOME study.<a class="elsevierStyleCrossRef" href="#bib0380">34</a> and the analysis of pooled data from different clinical trials do not appear to suggest a greater fracture rate with empagliflozin as compared to placebo.<a class="elsevierStyleCrossRef" href="#bib0385">35</a>InsulinRecommendations<ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0050">-We suggest the insulin treatment is related to an increased risk of fractures in patients with hypoglycemia and an increased incidence of falls (2ØØOO).</li></ul>EvidenceSeveral observational studies found a positive relation between insulin treatment and greater risk of fracture in both males and females with type 1 and 2 diabetes mellitus.<a class="elsevierStyleCrossRefs" href="#bib0275">13–39</a> These data should be interpreted with caution because of the presence of prescription bias, the greater use of insulin in patients with kidney failure and more advanced diabetes, and the possible coexistence of microvascular complications. However, the relationship of insulin treatment with fracture risk continues after adjustment for different confounding factors, but it cannot be ruled out that it is due to a greater risk of fall because of hypoglycemia, rather than to an effect of insulin itself.<a class="elsevierStyleCrossRef" href="#bib0410">40</a> On the other hand, observational studies do not support the relation between insulin treatment and fractures,<a class="elsevierStyleCrossRef" href="#bib0415">41</a> and even show a non-significant trend to a lower number of fractures.<a class="elsevierStyleCrossRef" href="#bib0220">2</a>ConclusionDiabetes is associated to a greater risk of fracture, and the effects on bone should therefore be considered an additional factor to be taken into account when antidiabetic treatment is selected. This is particularly relevant in patients with T2DM, in which different treatment options are available. While little evidence is available in some cases, the effect on BMD and risk of fracture of the most recently developed antidiabetic therapies, such as pioglitazone, incretin therapies, and SGLT2 inhibitors, is better defined. Except for the glitazone family, it may be stated that all other antidiabetic drug classes are reasonably safe for bone. Consideration of fracture risk associated to antidiabetic treatments may be particularly relevant in patients with diabetes who also have other risk factors for osteoporosis and fracture such as postmenopausal state, advanced age, and presence of chronic macrovascular and microvascular complications.FundingNo funding was received to conduct this study.Conflicts of interestThe authors state that they have no conflicts of interest in relation to preparation of this article.Note of authorsThis article is the executive summary of the complete document, which may be consulted at the web site of the Spanish Society of Endocrinology and Nutrition.<a class="elsevierStyleCrossRef" href="#bib0420">42</a>" "textoCompletoSecciones" => array:1 [ "secciones" => array:16 [ 0 => array:3 [ "identificador" => "xres834792" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Participants" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec830706" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres834793" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Participantes" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec830705" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Metformin" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Recommendations" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Evidence" ] ] ] 6 => array:3 [ "identificador" => "sec0025" "titulo" => "Glitazones" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Recommendations" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Evidence" ] ] ] 7 => array:3 [ "identificador" => "sec0040" "titulo" => "Sulfonylureas" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Recommendations" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Evidence" ] ] ] 8 => array:3 [ "identificador" => "sec0055" "titulo" => "GLP-1 receptor agonists (GLP-1 RAs) and DPP-4 inhibitors" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Recommendations" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Evidence" ] ] ] 9 => array:3 [ "identificador" => "sec0070" "titulo" => "SGLT2 inhibitors" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0075" "titulo" => "Recommendations" ] 1 => array:2 [ "identificador" => "sec0080" "titulo" => "Evidence" ] ] ] 10 => array:3 [ "identificador" => "sec0085" "titulo" => "Insulin" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0090" "titulo" => "Recommendations" ] 1 => array:2 [ "identificador" => "sec0095" "titulo" => "Evidence" ] ] ] 11 => array:2 [ "identificador" => "sec0100" "titulo" => "Conclusion" ] 12 => array:2 [ "identificador" => "sec0105" "titulo" => "Funding" ] 13 => array:2 [ "identificador" => "sec0110" "titulo" => "Conflicts of interest" ] 14 => array:2 [ "identificador" => "sec0115" "titulo" => "Note of authors" ] 15 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec830706" "palabras" => array:8 [ 0 => "Antidiabetic drugs" 1 => "Bone" 2 => "Osteoporosis" 3 => "Bone mineral density" 4 => "Fractures" 5 => "Bone metabolism" 6 => "Calciotropic hormones" 7 => "Bone markers" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec830705" "palabras" => array:8 [ 0 => "Fármacos antidiabéticos" 1 => "Hueso" 2 => "Osteoporosis" 3 => "Densidad mineral ósea" 4 => "Fracturas" 5 => "Metabolismo óseo" 6 => "Hormonas calciotropas" 7 => "Marcadores óseos" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "ObjectiveTo provide recommendations on the effect of antidiabetic drugs on bone fragility to help select the most adequate antidiabetic treatment, especially in diabetic patients with high risk of fracture. ParticipantsMembers of the Bone Metabolism Working Group of the Spanish Society of Endocrinology. MethodsThe GRADE system (Grading of Recommendations, Assessment, Development, and Evaluation) was used to establish both the strength of recommendations and the quality of evidence. A systematic search was made in MEDLINE (Pubmed) using the following terms associated to the name of each antidiabetic drug: AND “osteoporosis”, “fractures”, “bone mineral density”, “bone markers”, “calciotropic hormones”. Papers in English with publication date before 30 April 2016 were reviewed. Recommendations were jointly discussed by the Working Group. ConclusionsThe document summaries the data on the potential effects of antidiabetic drugs on bone metabolism and fracture risk." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Participants" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "ObjetivoProporcionar recomendaciones sobre el efecto de las diferentes terapias antidiabéticas en la fragilidad ósea con el fin de ayudar a seleccionar el tratamiento antidiabético más adecuado, especialmente en pacientes diabéticos con elevado riesgo de fractura. ParticipantesMiembros del Grupo de trabajo de Osteoporosis y Metabolismo Mineral de la SEEN. MétodosSe empleó el sistema Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) para establecer tanto la fuerza de las recomendaciones como el grado de evidencia. Se realizó una búsqueda sistemática en PubMed usando las siguientes palabras clave asociadas al nombre de cada tratamiento antidiabético: AND «osteoporosis», «fractures», «bone mineral density», «bone markers», «calciotropic hormones». Se revisaron artículos escritos en inglés con fecha de inclusio¿n hasta 30 de abril de 2016. Tras la formulación de las recomendaciones, estas se discutieron de forma conjunta por el Grupo de Trabajo. ConclusionesEste documento resume los datos acerca de los potenciales efectos de los diferentes tratamientos antidiabéticos sobre el metabolismo óseo y el riesgo de fractura." 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Gori" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/dc07-1736" "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2008" "volumen" => "31" "paginaInicial" => "199" "paginaFinal" => "203" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18024851" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0415" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nontraumatic fracture risk with diabetes mellitus and impaired fasting glucose in older white and black adults: the health, aging, and body composition study" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E.S. Strotmeyer" 1 => "J.A. Cauley" 2 => "A.V. Schwartz" 3 => "M.C. Nevitt" 4 => "H.E. Resnick" 5 => "D.C. 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Available from: <a href="http://www.seen.es/herramientasClinicas/guias/seen/guiaSeen.aspx">http://www.seen.es/herramientasClinicas/guias/seen/guiaSeen.aspx</a>." ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/25300180/00000064000000S1/v1_201704300024/S2530018017300343/v1_201704300024/en/main.assets" "Apartado" => null "PDF" => "https://static.elsevier.es/multimedia/25300180/00000064000000S1/v1_201704300024/S2530018017300343/v1_201704300024/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2530018017300343?idApp=UINPBA00004N"]

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Recommendations on the effect of antidiabetic drugs in bone

Recomendaciones sobre el efecto de los fármacos antidiabéticos en el hueso

Pedro Rozas-Morenoa,

Corresponding author

pedrorozasm@yahoo.es

Corresponding author.

, Rebeca Reyes-Garcíab, Esteban Jódar-Gimenoc, Mariela Varsavskyd, Inés Luque-Fernándeze, María Cortés-Berdoncesf, Manuel Muñoz-Torresg, Bone Metabolism Working Group of the Spanish Society of Endocrinology

a Sección de Endocrinología, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain

b Unidad de Endocrinología y Nutrición, Complejo Hospitalario Torrecárdenas; Servicio de Endocrinología, Clínica San Pedro, Almería, Spain

c Departamento de Endocrinología y Nutrición, Hospitales Universitarios Quirón Salud (Madrid Pozuelo, San Camilo, San José), Madrid, Spain

d Servicio de Endocrinología, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina

e Servicio de Endocrinología y Nutrición, Hospital Virgen de la Salud, Toledo, Spain

f Servicio de Endocrinología y Nutrición, Hospital Ruber Juan Bravo, Madrid, Spain

g UGC Endocrinología y Nutrición, Complejo Hospitalario Universitario de Granada, Departamento de Medicina, Universidad de Granada, Instituto de Investigación Biosanitaria de Granada, Granada, Spain

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Patients with diabetes have an increased risk of fracture&#44; and it is therefore important to understand the effect of antidiabetic drugs on bone&#46; Recommendations were made based on the Grading of Recommendations&#44; Assessment&#44; Development&#44; and Evaluation &#40;GRADE&#41; system to establish the strength of recommendations and the level of evidence&#46; A distinction is made between strong recommendations&#44; expressed as &#8220;We recommend&#8221; and number 1&#44; and weak recommendations&#44; expressed as &#8220;We suggest&#8221; and number 2&#46; The quality of evidence is expressed using symbols&#58; &#216;OOO indicates very low evidence&#59; &#216;&#216;OO low evidence&#59; &#216;&#216;&#216;O moderate evidence&#59; and &#216;&#216;&#216;&#216; high evidence&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Metformin</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Recommendations</span><p id="par0010" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0015" class="elsevierStylePara elsevierViewall">We suggest use of metformin as first choice drug to treat T2DM in patients with osteoporosis &#40;2&#216;&#216;OO&#41;&#46; Treatment with metformin causes a slightly increase in bone mineral density &#40;BMD&#41; &#40;2&#216;&#216;OO&#41;&#44; and its effect on risk of fracture is neutral or beneficial &#40;2&#216;&#216;OO&#41;&#46;</p></li></ul></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Evidence</span><p id="par0020" class="elsevierStylePara elsevierViewall">Few studies are available on the effects of metformin in humans&#46; Observational data show a protective effect on risk of fracture&#44; with a hazard ratio &#40;HR&#41; of 0&#46;7 &#40;95&#37; confidence interval &#91;CI&#93;&#58; 95&#37;&#58; 0&#46;6&#8211;0&#46;96&#41;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">1</span></a> and an odds ratio &#40;OR&#41; of 0&#46;8 &#40;95&#37; CI&#58; 0&#46;7&#8211;0&#46;93&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">2</span></a> In the A Diabetes Outcome Progression Trial &#40;ADOPT&#41;&#44; there were no beneficial effects of metformin on risk of fracture at 4 years of follow-up&#44; although levels of formation and resorption markers decreased at 12 months of treatment start&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">3&#44;4</span></a> As regards the effect of metformin on BMD&#44; the Borges et al&#46; study<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">5</span></a> found a slight increase in BMD in the lumbar spine&#44; total hip&#44; and distal third of radius in patients treated with metformin for 80 weeks&#46;</p></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Glitazones</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Recommendations</span><p id="par0025" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0030" class="elsevierStylePara elsevierViewall">We recommend that use of glitazones is avoided in women with diabetes and osteoporosis or with high fracture risk &#40;1&#216;&#216;&#216;O&#41;&#46; If used&#44; we recommend that such use is considered as a major risk factor for osteoporosis when risk of osteoporotic fracture is assessed &#40;1&#216;&#216;&#216;O&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0035" class="elsevierStylePara elsevierViewall">We recommend consideration that glitazones cause variable changes in remodeling markers &#40;BRM&#41; &#40;1&#216;&#216;&#216;O&#41; and decreases in lumbar&#44; femoral and appendicular BMD &#40;1&#216;&#216;&#216;O&#41;&#44; and double the risk of osteoporotic fractures&#44; especially in menopausal women &#40;1&#216;&#216;&#216;O&#41;&#46;</p></li></ul></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Evidence</span><p id="par0040" class="elsevierStylePara elsevierViewall">Data about the effect of rosiglitazone on BMD are conflicting &#40;reviewed in Lecka-Czernik<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">6</span></a>&#41;&#44; and a recent meta-analysis of 18 trials did not show a consistent pattern in BRM changes&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">7</span></a> Glitazones decrease BMD in lumbar spine &#40;difference &#8722;1&#46;1&#37;&#59; 95&#37; CI&#58; &#8722;1&#46;6 to &#8722;0&#46;7&#41;&#44; total hip &#40;&#8722;1&#46;0&#37;&#59; 95&#37; CI&#58; &#8722;1&#46;4 to &#8722;0&#46;6&#41;&#44; and forearm &#40;&#8722;0&#46;9&#37;&#59; 95&#37; CI&#58; &#8722;1&#46;6 to &#8722;0&#46;3&#41;&#46; Changes in BMD persist one year after treatment discontinuation&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">7</span></a> As regards risk of fracture&#44; observational studies have shown increases &#40;pioglitazone&#58; OR 2&#46;59&#59; 95&#37; CI&#58; 0&#46;96&#8211;7&#46;01&#44; and rosiglitazone&#58; OR 2&#46;38&#59; 95&#37; CI&#58; 1&#46;39&#8211;4&#46;09&#41; related to age &#40;greater in subjects from 65 years of age&#41; and to longer treatment duration&#46; The risk is higher in females and in subjects with prior fractures&#46; An increased risk has also been reported in males &#40;observational studies&#44; reviewed in Lecka-Czernik<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">6</span></a>&#41;&#46; By contrast&#44; in a case-control study conducted in an Asian population&#44; glitazones were associated to an increased risk of fracture&#44; especially in women under 64 years of age &#40;OR 1&#46;74&#8211;2&#46;58&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">8</span></a> In the ADOPT study<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">3</span></a>&#44; rosiglitazone monotherapy was associated to a higher fracture rate &#40;9&#46;30&#37; in 5 years&#41; as compared to metformin &#40;5&#46;08&#37;&#41; and glibenclamide &#40;3&#46;47&#37;&#41; &#40;RR 1&#46;81 and 2&#46;13 respectively&#41;&#46; Pioglitazone also increases fracture risk in women &#40;1&#46;9 versus 1&#46;1 fractures per 100 patient-years&#41; &#40;reviewed in Lecka-Czernik<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">6</span></a> and McCulloc<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">9</span></a>&#41;&#46; In the Action to Control Cardiovascular Risk in Diabetes &#40;ACCORD&#41; study&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">10</span></a> use of glitazones &#40;74&#37; rosiglitazone&#44; 13&#37; pioglitazone&#41; increased the fracture rate in women only from one year of use &#40;HR &#8805;2&#41;&#44; and risk decreased from one year after drug discontinuation&#46; A meta-analysis<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">11</span></a> of controlled studies &#40;13&#44;715 participants&#41; and observational studies &#40;31&#44;679 participants&#41; confirmed that glitazones double the risk of fracture&#44; but only in females&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Sulfonylureas</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Recommendations</span><p id="par0045" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0015"><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">We suggest that treatment with sulfonylureas may increase risk of hip fracture in patients over 65 years of age and in subjects with documented hypoglycemia &#40;2&#216;&#216;OO&#41;&#44; and also the incidence of falls in institutionalized patients &#40;2&#216;&#216;OO&#41;&#46;</p></li></ul></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Evidence</span><p id="par0055" class="elsevierStylePara elsevierViewall">A prospective&#44; randomized study reported an increase in BMD related to use of sulfonylureas &#40;SU&#41;&#44; mediated by increased endogenous C-peptide and proinsulin levels&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">12</span></a> On the other hand&#44; a higher risk of hypoglycemia may increase falls and risk of fracture&#46; In a case-control study&#44; authors reported a lower risk of hip fracture in patients treated with SU&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">2</span></a> In another case-control study with less cases&#44; there was no association between treatment with SU and risk of fracture &#40;OR 0&#46;77&#59; 95&#37; CI&#58; 0&#46;44&#8211;1&#46;37&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">13</span></a> Analysis of the risk of vertebral fracture showed that treatment with SU was a protective factor in females but not in males&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">13</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">A systematic review conducted in 2013 concluded that no adequate evidence is available to state that a relationship exists between use of SU and risk of fracture&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">14</span></a> However&#44; in a subsequent observational study in patients with diabetes older than 65 years&#44; use of SU was associated to greater risk of hip fracture &#40;OR 1&#46;46&#59; 95&#37; CI&#58; 1&#46;17&#8211;1&#46;82&#41; both in females and males&#46; Risk of hip fracture is higher in patients with documented hypoglycemia &#40;OR 2&#46;42&#59; 95&#37; CI&#58; 1&#46;35&#8211;4&#46;34&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">15</span></a> In institutionalized patients&#44; start of treatment with SU was not associated to greater risk of fracture&#44; but was related to higher risk of fall &#40;HR 1&#46;13&#59; 95&#37; CI&#58; 1&#46;00&#8211;1&#46;26&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">16</span></a></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">GLP-1 receptor agonists &#40;GLP-1 RAs&#41; and DPP-4 inhibitors</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Recommendations</span><p id="par0065" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0020"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0070" class="elsevierStylePara elsevierViewall">We think that use of DPP-4 inhibitors does not modify risk of fracture &#40;1&#216;&#216;&#216;O&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">-</span><p id="par0075" class="elsevierStylePara elsevierViewall">We think that treatment with GLP-1 RAs &#40;exenatide&#44; liraglutide&#41; does not affect BMD &#40;1&#216;&#216;OO&#41; or risk of fracture &#40;1&#216;&#216;&#216;O&#41;&#46;</p></li></ul></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Evidence</span><p id="par0080" class="elsevierStylePara elsevierViewall">In the study Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus &#40;SAVOR&#41;&#8211;Thrombolysis in Myocardial Infarction &#40;TIMI&#41;&#44; there were no differences in risk of fracture between saxagliptin and placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">17</span></a> These results were confirmed by a cohort study&#44;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">18</span></a> conducted from 2007 to 2012&#44; which found no differences in risk of fracture between patients treated with DPP-4 inhibitors and controls &#40;adjusted HR 0&#46;89&#59; 95&#37; CI&#58; 0&#46;71&#8211;1&#46;13&#41;&#46; Treatment with DPP-4 inhibitors did not increase the risk as compared to other non-insulin antidiabetic therapies &#40;HR 1&#46;03&#59; 95&#37; CI&#58; 0&#46;92&#8211;1&#46;15&#41;&#46; However&#44; as admitted by the authors&#44; treatment duration may have been too short to determine the effect&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">18</span></a> These results are in contrast with those of a meta-analysis of clinical trials<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">19</span></a> that showed a 40&#37; decrease in fracture risk in users of DPP-4 inhibitors as compared to active treatment or placebo&#46; Identification of fractures as adverse effects rather than as the primary objective&#44; the low number of fractures seen&#44; and use of different comparators may have influenced the results&#46; In a population study<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">20</span></a> of patients with T2DM &#40;mean age&#44; 52 years&#41;&#44; use of sitagliptin was not related to higher risk of fracture&#44; while a greater risk was seen in patients treated with sulfonylureas or insulin&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">In 66 patients with T2DM treated with metformin&#44; treatment with exenatide &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>33&#41; or insulin glargine &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>33&#41; for 44 weeks did not affect BMD&#44; BRMs&#44; or calciotropic hormones&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">21</span></a> A subanalysis of 61 patients from the LEAD 3 study&#44;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">22</span></a> there were no significant changes from baseline in the BMD of patients given liraglutide or glimepiride after 104 weeks of treatment&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Different meta-analyses<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">23&#44;24</span></a> and cohort studies have confirmed that treatment with GLP-1 RAs does not affect fracture risk&#46; In a cohort study&#44;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">25</span></a> a lower risk of fracture was not seen in patients treated with GLP-1 RAs as compared to those who had never received them &#40;adjusted HR 0&#46;97&#59; 95&#37; CI&#58; 0&#46;72&#8211;1&#46;32&#41;&#46; No relationship was also seen between risk of failure and cumulative dose&#46; These findings were confirmed in another case-control study<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">26</span></a> where treatment with GLP-1 RAs was not associated to a decreased risk of fracture &#40;OR 1&#46;16&#59; 95&#37; CI&#58; 0&#46;83&#8211;1&#46;63&#41;&#46; No relationship was also seen between current treatment with GLP-1 RAs and risk of osteoporotic fracture &#40;OR 0&#46;78&#59; 95&#37; CI&#58; 0&#46;44&#8211;1&#46;39&#41;&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">In the meta-analysis by Su et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">24</span></a> treatment with liraglutide was associated to a decrease in the risk of incident fractures &#40;Mantel-Haenszel OR 0&#46;38&#59; 95&#37; CI&#58; 0&#46;17&#8211;0&#46;87&#41;&#44; while exenatide was associated to an increased risk of incident fractures &#40;Mantel-Haenszel OR 2&#46;09&#59; 95&#37; CI&#58; 1&#46;03&#8211;4&#46;21&#41;&#46; According to the authors&#44; the greater homology of liraglutide with human GLP-1&#44; as well as a longer half-life&#44; could explain the different effects on risk of fracture&#46; However&#44; the low number of fractures reported and the short duration of the studies limit the strength of conclusions&#46;</p></span></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">SGLT2 inhibitors</span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Recommendations</span><p id="par0100" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0025"><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">-</span><p id="par0105" class="elsevierStylePara elsevierViewall">We recommend consideration of the fact that use of canagliflozin is associated to increases in BRMs and to a slight decrease of BMD in total hip &#40;1&#216;&#216;OO&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">-</span><p id="par0110" class="elsevierStylePara elsevierViewall">We suggest that treatment with empagliflozin may increase urinary bone resorption markers with no significant increase in number of fractures &#40;2&#216;&#216;OO&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">-</span><p id="par0115" class="elsevierStylePara elsevierViewall">We suggest caution when dapagliflozin and canagliflozin are used in some groups of patients&#44; because they may increase risk of fracture &#40;2&#216;&#216;OO&#41;&#46;</p></li></ul></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Evidence</span><p id="par0120" class="elsevierStylePara elsevierViewall">Use of canagliflozin and dapagliflozin has been related to a mild increase in phosphate&#44; magnesium&#44; and iPTH levels&#44; with no significant changes in serum calcium levels and a slight decrease in 1&#44;25-dihydroxyvitamin D levels&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">27</span></a> In a randomized&#44; double-blind study&#44;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">28</span></a> treatment with canagliflozin was associated to decreased serum estradiol levels&#44; a significant increase in BRMs at 52 weeks of treatment&#44; and a decrease in total hip BMD &#40;&#8722;0&#46;9&#37; and &#8722;1&#46;2&#37; for canagliflozin 100<span class="elsevierStyleHsp" style=""></span>mg and 300<span class="elsevierStyleHsp" style=""></span>mg respectively&#41;&#46; Changes seen in BRMs and BMD are partly explained by the weight loss seen&#46; No significant changes were found in the bone resistance parameters tested&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">28</span></a> Treatment with dapagliflozin has not been associated to significant changes in BRMs&#44; 25-hydroxyvitamin A &#40;25OHD&#41; or BMD in the different regions analzed&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">29</span></a> No significant changes have been reported in serum calcium&#44; phosphorus&#44; 25OHD&#44; iPTH or alkaline phosphatase with empagliflozin&#44; but the 25<span class="elsevierStyleHsp" style=""></span>mg dose did slightly but significantly increase urinary levels of amino-terminal collagen crosslinks &#40;NTX&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">30</span></a> As regards BMD&#44; use of empagliflozin does not appear to be associated to clinically significant changes based on the results of a substudy of the comparative clinical trial with glimepiride&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">30</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">With regard to fractures&#44; the risk may be increase in some patient subgroups&#44; but limited data are available&#46; Phase IIb&#47;III studies with dapagliflozin have not shown a significant increase in fracture risk&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">31</span></a> However&#44; among patients with moderate kidney failure&#44; 9&#46;4&#37; and 6&#37; of those treated with dapagliflozin 10<span class="elsevierStyleHsp" style=""></span>mg and 5<span class="elsevierStyleHsp" style=""></span>mg respectively sustained a fracture during treatment at 104 weeks&#44; while subjects given placebo sustained no fractures&#46; After excluding fractures in not typically osteoporotic locations&#44; 7&#37; of patients on dapagliflozin 10<span class="elsevierStyleHsp" style=""></span>mg sustained fractures&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">32</span></a> In a recent meta-analysis of nine clinical trials&#44; use canagliflozina was related to an increased incidence of fractures&#44; mainly in subjects participating in the Canagliflozin Cardiovascular Assessment Study &#40;CANVAS&#41; &#40;4&#37; canagliflozin vs 2&#46;6&#37; placebo&#41;&#44; representing an older population with high cardiovascular risk&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">33</span></a> Mean drug exposure was 85 weeks&#44; and although the risk appears in the first weeks of treatment&#44; it seems to continue over time&#46; Finally&#44; the results of the EMPA-REG OUTCOME study&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">34</span></a> and the analysis of pooled data from different clinical trials do not appear to suggest a greater fracture rate with empagliflozin as compared to placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">35</span></a></p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Insulin</span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Recommendations</span><p id="par0130" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0030"><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">-</span><p id="par0135" class="elsevierStylePara elsevierViewall">We suggest the insulin treatment is related to an increased risk of fractures in patients with hypoglycemia and an increased incidence of falls &#40;2&#216;&#216;OO&#41;&#46;</p></li></ul></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Evidence</span><p id="par0140" class="elsevierStylePara elsevierViewall">Several observational studies found a positive relation between insulin treatment and greater risk of fracture in both males and females with type 1 and 2 diabetes mellitus&#46;<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">13&#8211;39</span></a> These data should be interpreted with caution because of the presence of prescription bias&#44; the greater use of insulin in patients with kidney failure and more advanced diabetes&#44; and the possible coexistence of microvascular complications&#46; However&#44; the relationship of insulin treatment with fracture risk continues after adjustment for different confounding factors&#44; but it cannot be ruled out that it is due to a greater risk of fall because of hypoglycemia&#44; rather than to an effect of insulin itself&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">40</span></a> On the other hand&#44; observational studies do not support the relation between insulin treatment and fractures&#44;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">41</span></a> and even show a non-significant trend to a lower number of fractures&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">2</span></a></p></span></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Conclusion</span><p id="par0145" class="elsevierStylePara elsevierViewall">Diabetes is associated to a greater risk of fracture&#44; and the effects on bone should therefore be considered an additional factor to be taken into account when antidiabetic treatment is selected&#46; This is particularly relevant in patients with T2DM&#44; in which different treatment options are available&#46; While little evidence is available in some cases&#44; the effect on BMD and risk of fracture of the most recently developed antidiabetic therapies&#44; such as pioglitazone&#44; incretin therapies&#44; and SGLT2 inhibitors&#44; is better defined&#46; Except for the glitazone family&#44; it may be stated that all other antidiabetic drug classes are reasonably safe for bone&#46; Consideration of fracture risk associated to antidiabetic treatments may be particularly relevant in patients with diabetes who also have other risk factors for osteoporosis and fracture such as postmenopausal state&#44; advanced age&#44; and presence of chronic macrovascular and microvascular complications&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Funding</span><p id="par0150" class="elsevierStylePara elsevierViewall">No funding was received to conduct this study&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Conflicts of interest</span><p id="par0155" class="elsevierStylePara elsevierViewall">The authors state that they have no conflicts of interest in relation to preparation of this article&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Note of authors</span><p id="par0160" class="elsevierStylePara elsevierViewall">This article is the executive summary of the complete document&#44; which may be consulted at the web site of the Spanish Society of Endocrinology and Nutrition&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">42</span></a></p></span></span>"
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            0 => "Antidiabetic drugs"
            1 => "Bone"
            2 => "Osteoporosis"
            3 => "Bone mineral density"
            4 => "Fractures"
            5 => "Bone metabolism"
            6 => "Calciotropic hormones"
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            0 => "F&#225;rmacos antidiab&#233;ticos"
            1 => "Hueso"
            2 => "Osteoporosis"
            3 => "Densidad mineral &#243;sea"
            4 => "Fracturas"
            5 => "Metabolismo &#243;seo"
            6 => "Hormonas calciotropas"
            7 => "Marcadores &#243;seos"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To provide recommendations on the effect of antidiabetic drugs on bone fragility to help select the most adequate antidiabetic treatment&#44; especially in diabetic patients with high risk of fracture&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Participants</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Members of the Bone Metabolism Working Group of the Spanish Society of Endocrinology&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">The GRADE system &#40;Grading of Recommendations&#44; Assessment&#44; Development&#44; and Evaluation&#41; was used to establish both the strength of recommendations and the quality of evidence&#46; A systematic search was made in MEDLINE &#40;Pubmed&#41; using the following terms associated to the name of each antidiabetic drug&#58; AND &#8220;osteoporosis&#8221;&#44; &#8220;fractures&#8221;&#44; &#8220;bone mineral density&#8221;&#44; &#8220;bone markers&#8221;&#44; &#8220;calciotropic hormones&#8221;&#46; Papers in English with publication date before 30 April 2016 were reviewed&#46; Recommendations were jointly discussed by the Working Group&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">The document summaries the data on the potential effects of antidiabetic drugs on bone metabolism and fracture risk&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Proporcionar recomendaciones sobre el efecto de las diferentes terapias antidiab&#233;ticas en la fragilidad &#243;sea con el fin de ayudar a seleccionar el tratamiento antidiab&#233;tico m&#225;s adecuado&#44; especialmente en pacientes diab&#233;ticos con elevado riesgo de fractura&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Participantes</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Miembros del Grupo de trabajo de Osteoporosis y Metabolismo Mineral de la SEEN&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">M&#233;todos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se emple&#243; el sistema <span class="elsevierStyleItalic">Grading of Recommendations&#44; Assessment&#44; Development&#44; and Evaluation</span> &#40;GRADE&#41; para establecer tanto la fuerza de las recomendaciones como el grado de evidencia&#46; Se realiz&#243; una b&#250;squeda sistem&#225;tica en PubMed usando las siguientes palabras clave asociadas al nombre de cada tratamiento antidiab&#233;tico&#58; AND &#171;osteoporosis&#187;&#44; &#171;fractures&#187;&#44; &#171;bone mineral density&#187;&#44; &#171;bone markers&#187;&#44; &#171;calciotropic hormones&#187;&#46; Se revisaron art&#237;culos escritos en ingl&#233;s con fecha de inclusio¿n hasta 30 de abril de 2016&#46; Tras la formulaci&#243;n de las recomendaciones&#44; estas se discutieron de forma conjunta por el Grupo de Trabajo&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Este documento resume los datos acerca de los potenciales efectos de los diferentes tratamientos antidiab&#233;ticos sobre el metabolismo &#243;seo y el riesgo de fractura&#46;</p></span>"
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Article information

ISSN: 25300180
Original language: English

DOI:10.1016/j.endien.2016.11.002

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Year/Month	Html	Pdf	Total

2024 November	4	0	4
2024 October	39	10	49
2024 September	45	29	74
2024 August	44	13	57
2024 July	42	6	48
2024 June	52	4	56
2024 May	35	7	42
2024 April	31	6	37
2024 March	70	5	75
2024 February	79	3	82
2024 January	64	0	64
2023 December	51	6	57
2023 November	78	3	81
2023 October	82	6	88
2023 September	55	5	60
2023 August	29	1	30
2023 July	16	2	18
2023 June	33	1	34
2023 May	34	0	34
2023 April	42	3	45
2023 March	31	6	37
2023 February	30	1	31
2023 January	20	2	22
2022 December	22	3	25
2022 November	29	9	38
2022 October	27	8	35
2022 September	16	17	33
2022 August	17	14	31
2022 July	15	7	22
2022 June	15	4	19
2022 May	36	5	41
2022 April	29	10	39
2022 March	29	9	38
2022 February	37	6	43
2022 January	59	9	68
2021 December	62	13	75
2021 November	53	12	65
2021 October	58	23	81
2021 September	61	18	79
2021 August	40	14	54
2021 July	19	14	33
2021 June	25	23	48
2021 May	41	21	62
2021 April	91	15	106
2021 March	45	43	88
2021 February	37	7	44
2021 January	54	9	63
2020 December	41	10	51
2020 November	37	7	44
2020 October	13	8	21
2020 September	28	9	37
2020 August	33	6	39
2020 July	14	5	19
2020 June	19	7	26
2020 May	36	5	41
2020 April	24	12	36
2020 March	26	8	34
2020 February	19	2	21
2020 January	20	4	24
2019 December	15	8	23
2019 November	7	5	12
2019 October	8	1	9
2019 September	13	2	15
2019 August	9	1	10
2019 July	10	19	29
2019 June	18	5	23
2019 May	96	1	97
2019 April	46	26	72
2019 March	2	4	6
2019 February	6	2	8
2019 January	4	2	6
2018 December	2	3	5
2018 November	9	2	11
2018 October	9	7	16
2018 September	6	0	6
2018 August	2	8	10
2018 July	8	0	8
2018 June	3	2	5
2018 May	7	0	7
2018 April	4	1	5
2018 March	6	1	7
2018 February	8	0	8
2018 January	2	0	2
2017 December	3	0	3
2017 November	10	1	11
2017 October	5	0	5
2017 September	15	2	17
2017 August	1	0	1

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