{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T05:07:46Z","timestamp":1793250466528,"version":"4.5.0"},"reference-count":75,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["PP00B-114864"],"award-info":[{"award-number":["PP00B-114864"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007214","name":"Velux Stiftung","doi-asserted-by":"publisher","award":["441"],"award-info":[{"award-number":["441"]}],"id":[{"id":"10.13039\/100007214","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007252","name":"Baugarten Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007252","id-type":"DOI","asserted-by":"publisher"}]},{"name":"ECTS Academy Personal Reserach Grant"},{"DOI":"10.13039\/501100006447","name":"University of Zurich","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100006447","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Calcif Tissue Int"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Proton-pump inhibitors (PPI) are widely used among older adults and PPI intake has been associated with increased fracture risk. However, their association with bone microarchitecture and strength remains unclear as prior clinical PPI studies were restricted to lower-resolution bone imaging techniques such as DXA. Using high-resolution peripheral computed tomography (HR-pQCT), we prospectively investigated whether long-term PPI use was associated with changes in volumetric bone mineral densities, bone microarchitecture, and strength in older patients. 189 patients aged\u2009\u2265\u200960\u00a0years (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200924 persistent PPI users [p-PPI user], and\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009165 non-PPI users), enrolled as part of a 2-year vitamin D RCT, underwent HR-pQCT scanning of the tibia and radius at 0 and 2\u00a0years. Bone volumetric density (vBMD), microarchitectural and strength parameters were computed and adjusted linear regression models without and with adjustments, including age, sex, BMI, and treatment groups, were employed to compare changes between p-PPI users and non-PPI users. At baseline, both groups were comparable with respect to age, vBMDs, bone microarchitecture, and sex. During follow-up, p-PPI users lost significantly more distal tibial total volumetric BMD (\u0394Tt.BMD: \u2212\u00a08.58 vs. \u2212\u00a02.45\u00a0mg\/cm\n                    <jats:sup>3<\/jats:sup>\n                    ,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.012) and cortical volumetric BMD (\u0394Ct.BMD, \u2212\u00a028.96 vs. -14.07\u00a0mg\/cm\n                    <jats:sup>3<\/jats:sup>\n                    ,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.005), and showed a significantly greater loss in tibial bone strength (\u0394stiffness \u2212\u00a04848.1 vs. 20.7 N\/mm,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.029; \u0394failure load \u2212\u00a0204.5 vs. 16.7 N,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.026) than non-PPI users. At the radius, p-PPI users showed over the 2\u00a0years significantly greater increases in cortical porosity and intracortical pore diameter than non-PPI users (\u0394Ct.Po,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.005; \u0394Ct.PoDm,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.009). Long-term PPI intake was associated with a significant decline in cortical microarchitecture at the radius and with a significant deterioration of volumetric bone mineral density and strength at the tibia in older patients.\n                  <\/jats:p>","DOI":"10.1007\/s00223-025-01420-7","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T16:35:34Z","timestamp":1761150934000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Regular Proton-Pump Inhibitor Intake is Associated with Deterioration of Peripheral Bone Mineral Density, Microarchitecture, and Strength in Older Patients as Assessed by High-Resolution Peripheral Quantitative Computed Tomography (HR-pQCT)"],"prefix":"10.1007","volume":"116","author":[{"given":"Ursula","family":"Heilmeier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Siegenthaler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursina","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Boensch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Kistler-Fischbacher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"de Godoi Rezende Costa Molino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert","family":"van Rietbergen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9","family":"Rizzoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Theiler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Egli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike Annette","family":"Bischoff-Ferrari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,22]]},"reference":[{"issue":"8","key":"1420_CR1","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1007\/s00198-013-2348-z","volume":"24","author":"K \u00c5kesson","year":"2013","unstructured":"IOF Fracture Working Group, \u00c5kesson K, Marsh D, Mitchell PJ, McLellan AR, Stenmark J, Pierroz DD, Kyer C, Cooper C (2013) Capture the Fracture: a Best Practice Framework and global campaign to break the fragility fracture cycle. Osteoporos Int 24(8):2135\u20132152","journal-title":"Osteoporos Int"},{"issue":"4","key":"1420_CR2","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1097\/BOR.0000000000000300","volume":"28","author":"D Bliuc","year":"2016","unstructured":"Bliuc D, Center JR (2016) Determinants of mortality risk following osteoporotic fractures. Curr Opin Rheumatol 28(4):413\u2013419","journal-title":"Curr Opin Rheumatol"},{"key":"1420_CR3","doi-asserted-by":"crossref","unstructured":"Tarride J-E, Burke N, Leslie WD, Morin SN, Adachi JD, Papaioannou A, Bessette L, Brown JP, Pericleous L, Muratov S, Hopkins RB. Loss of health related quality of life following low-trauma fractures in the elderly. BMC Geriatr [Internet]. 2016 [cited 2020 Sep 21];16. https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC4837505\/","DOI":"10.1186\/s12877-016-0259-5"},{"issue":"37","key":"1420_CR4","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ejim.2016.10.007","volume":"1","author":"V Savarino","year":"2017","unstructured":"Savarino V, Dulbecco P, de Bortoli N, Ottonello A, Savarino E (2017) The appropriate use of proton pump inhibitors (PPIs): Need for a reappraisal. Eur J Intern Med 1(37):19\u201324","journal-title":"Eur J Intern Med"},{"key":"1420_CR5","unstructured":"IMS Institute for Healthcare Informatics, Aitken M. Declining Medicine Use and Costs: For Better or Worse? A Review of the Use of Medicines in the United Statesin 2012. Burlington, MA; 2013."},{"key":"1420_CR6","unstructured":"IMS Institute for Healthcare Informatics. Medicine Use and Spending in the U.S. A Review of 2017 and Outlook to 2022. Parsippany, NJ; 2018."},{"key":"1420_CR7","unstructured":"Hoffmann F, Glaeske G, Schiemann G. Increased prescribing of proton pump inhibitors in ambulatory care over the years 2005 - 2013 [Internet]. Z Gastroenterol. Z Gastroenterol; 2015 [cited 2020 Sep 21]. https:\/\/pubmed.ncbi.nlm.nih.gov\/25251751\/"},{"issue":"20","key":"1420_CR8","doi-asserted-by":"crossref","first-page":"5052","DOI":"10.1111\/febs.12478","volume":"280","author":"J Costa-Rodrigues","year":"2013","unstructured":"Costa-Rodrigues J, Reis S, Teixeira S, Lopes S, Fernandes MH (2013) Dose-dependent inhibitory effects of proton pump inhibitors on human osteoclastic and osteoblastic cell activity. FEBS J 280(20):5052\u20135064","journal-title":"FEBS J"},{"issue":"5","key":"1420_CR9","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s00774-015-0699-6","volume":"34","author":"E Bahtiri","year":"2016","unstructured":"Bahtiri E, Islami H, Hoxha R, Qorraj-Bytyqi H, Rexhepi S, Hoti K, Tha\u00e7i K, Tha\u00e7i S, Karakulak \u00c7 (2016) Esomeprazole use is independently associated with significant reduction of BMD: 1-year prospective comparative safety study of four proton pump inhibitors. J Bone Miner Metab 34(5):571\u2013579","journal-title":"J Bone Miner Metab"},{"issue":"2","key":"1420_CR10","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.jocd.2018.06.008","volume":"22","author":"YH Shin","year":"2019","unstructured":"Shin YH, Gong HS, Baek GH (2019) Lower trabecular bone score is associated with the use of proton pump inhibitors. J Clin Densitom 22(2):236\u2013242","journal-title":"J Clin Densitom"},{"issue":"4","key":"1420_CR11","doi-asserted-by":"crossref","first-page":"1161","DOI":"10.1007\/s00198-012-2112-9","volume":"24","author":"L-A Fraser","year":"2013","unstructured":"Fraser L-A, Leslie WD, Targownik LE, Papaioannou A, Adachi JD, CaMos Research Group (2013) The effect of proton pump inhibitors on fracture risk: report from the Canadian Multicenter Osteoporosis Study. Osteoporos Int 24(4):1161\u20131168","journal-title":"Osteoporos Int"},{"issue":"6","key":"1420_CR12","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1007\/s11894-012-0290-4","volume":"14","author":"Y-X Yang","year":"2012","unstructured":"Yang Y-X (2012) Chronic proton pump inihibitor therapy and calcium metabolism. Curr Gastroenterol Rep 14(6):473\u2013479","journal-title":"Curr Gastroenterol Rep"},{"issue":"1","key":"1420_CR13","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1007\/s00198-015-3365-x","volume":"27","author":"B Zhou","year":"2016","unstructured":"Zhou B, Huang Y, Li H, Sun W, Liu J (2016) Proton-pump inhibitors and risk of fractures: an update meta-analysis. Osteoporos Int 27(1):339\u2013347","journal-title":"Osteoporos Int"},{"issue":"24","key":"1420_CR14","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.1001\/jama.296.24.2947","volume":"296","author":"YX Yang","year":"2006","unstructured":"Yang YX, Lewis JD, Epstein S, Metz DC, American Medical Association (2006) Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 296(24):2947\u20132953","journal-title":"JAMA"},{"issue":"4","key":"1420_CR15","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.annepidem.2014.01.004","volume":"24","author":"AL Adams","year":"2014","unstructured":"Adams AL, Black MH, Zhang JL, Shi JM, Jacobsen SJ (2014) Proton-pump inhibitor use and hip fractures in men: a population-based case-control study. Ann Epidemiol 24(4):286\u2013290","journal-title":"Ann Epidemiol"},{"key":"1420_CR16","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.bone.2015.08.024","volume":"81","author":"MMC van der Hoorn","year":"2015","unstructured":"van der Hoorn MMC, Tett SE, de Vries OJ, Dobson AJ, Peeters GMEE (Geeske) (2015) The effect of dose and type of proton pump inhibitor use on risk of fractures and osteoporosis treatment in older Australian women: A prospective cohort study. Bone 81:675\u2013682","journal-title":"Bone"},{"issue":"218","key":"1420_CR17","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.lfs.2018.12.058","volume":"1","author":"J Liu","year":"2019","unstructured":"Liu J, Li X, Fan L, Yang J, Wang J, Sun J, Wang Z (2019) Proton pump inhibitors therapy and risk of bone diseases: an update meta-analysis. Life Sci 1(218):213\u2013223","journal-title":"Life Sci"},{"issue":"4","key":"1420_CR18","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1053\/j.gastro.2018.11.023","volume":"156","author":"KE Hansen","year":"2019","unstructured":"Hansen KE, Nieves JW, Nudurupati S, Metz DC, Perez MC (2019) Dexlansoprazole and esomeprazole do not affect bone homeostasis in healthy postmenopausal women. Gastroenterology 156(4):926-934.e6","journal-title":"Gastroenterology"},{"issue":"3","key":"1420_CR19","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1053\/j.gastro.2009.11.014","volume":"138","author":"LE Targownik","year":"2010","unstructured":"Targownik LE, Lix LM, Leung S, Leslie WD (2010) Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology 138(3):896\u2013904","journal-title":"Gastroenterology"},{"issue":"3","key":"1420_CR20","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1053\/j.gastro.2019.05.056","volume":"157","author":"P Moayyedi","year":"2019","unstructured":"Moayyedi P, Eikelboom JW, Bosch J, Connolly SJ, Dyal L, Shestakovska O, Leong D, Anand SS, St\u00f6rk S, Branch KRH, Bhatt DL, Verhamme PB, O\u2019Donnell M, Maggioni AP, Lonn EM, Piegas LS, Ertl G, Keltai M, Bruns NC, Muehlhofer E, Dagenais GR, Kim J-H, Hori M, Steg PG, Hart RG, Diaz R, Alings M, Widimsky P, Avezum A, Probstfield J, Zhu J, Liang Y, Lopez-Jaramillo P, Kakkar AK, Parkhomenko AN, Ryden L, Pogosova N, Dans AL, Lanas F, Commerford PJ, Torp-Pedersen C, Guzik TJ, Vinereanu D, Tonkin AM, Lewis BS, Felix C, Yusoff K, Metsarinne KP, Fox KAA, Yusuf S (2019) Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology 157(3):682-691.e2","journal-title":"Gastroenterology"},{"issue":"6","key":"1420_CR21","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1002\/pds.4406","volume":"27","author":"BN Harding","year":"2018","unstructured":"Harding BN, Weiss NS, Walker RL, Larson EB, Dublin S (2018) Proton pump inhibitor use and the risk of fractures among an older adult cohort. Pharmacoepidemiol Drug Saf 27(6):596\u2013603","journal-title":"Pharmacoepidemiol Drug Saf"},{"issue":"1","key":"1420_CR22","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1038\/ajg.2016.481","volume":"112","author":"L Targownik","year":"2017","unstructured":"Targownik L, Goertzen A, Luo Y, Leslie W (2017) Long-term proton pump inhibitor use is not associated with changes in bone strength and structure. Am J Gastroenterol 112(1):95\u2013101","journal-title":"Am J Gastroenterol"},{"issue":"2","key":"1420_CR23","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s11914-013-0142-7","volume":"11","author":"KK Nishiyama","year":"2013","unstructured":"Nishiyama KK, Shane E (2013) Clinical Imaging of Bone Microarchitecture with HR-pQCT. Curr Osteoporos Rep 11(2):147\u2013155","journal-title":"Curr Osteoporos Rep"},{"key":"1420_CR24","doi-asserted-by":"crossref","unstructured":"Bischoff-Ferrari HA, Orav EJ, Egli A, Dawson-Hughes B, Fischer K, Staehelin HB, Rizzoli R, Hodler J, von Eckardstein A, Freystaetter G, Meyer U, Guggi T, Burckhardt P, Schietzel S, Chocano-Bedoya P, Theiler R, Willett WC, Felson D. Recovery after unilateral knee replacement due to severe osteoarthritis and progression in the contralateral knee: a randomised clinical trial comparing daily 2000 IU versus 800 IU vitamin D. RMD Open [Internet]. 2018 [cited 2020 Sep 20];4(2). https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6045766\/","DOI":"10.1136\/rmdopen-2018-000678"},{"issue":"5","key":"1420_CR25","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/0021-9681(87)90171-8","volume":"40","author":"ME Charlson","year":"1987","unstructured":"Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40(5):373\u2013383","journal-title":"J Chronic Dis"},{"issue":"2","key":"1420_CR26","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.jclinepi.2010.03.013","volume":"64","author":"N Bellamy","year":"2011","unstructured":"Bellamy N, Wilson C, Hendrikz J, Whitehouse SL, Patel B, Dennison S, Davis T, EDC Study Group (2011) Osteoarthritis Index delivered by mobile phone (m-WOMAC) is valid, reliable, and responsive. J Clin Epidemiol 64(2):182\u2013190","journal-title":"J Clin Epidemiol"},{"issue":"9","key":"1420_CR27","doi-asserted-by":"crossref","first-page":"604","DOI":"10.7326\/0003-4819-150-9-200905050-00006","volume":"150","author":"AS Levey","year":"2009","unstructured":"Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J (2009) CKD-EPI (chronic kidney disease epidemiology collaboration). A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604\u2013612","journal-title":"Ann Intern Med"},{"issue":"1","key":"1420_CR28","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1093\/ajcn\/nqz081","volume":"110","author":"S Schietzel","year":"2019","unstructured":"Schietzel S, Fischer K, Brugger P, Orav EJ, Renerts K, Gagesch M, Freystaetter G, St\u00e4helin HB, Egli A, Bischoff-Ferrari HA (2019) Effect of 2000 IU compared with 800 IU vitamin D on cognitive performance among adults age 60 years and older: a randomized controlled trial. Am J Clin Nutr 110(1):246\u2013253","journal-title":"Am J Clin Nutr"},{"issue":"12","key":"1420_CR29","doi-asserted-by":"crossref","first-page":"6508","DOI":"10.1210\/jc.2005-1258","volume":"90","author":"S Boutroy","year":"2005","unstructured":"Boutroy S, Bouxsein ML, Munoz F, Delmas PD (2005) In vivo assessment of trabecular bone microarchitecture by high-resolution peripheral quantitative computed tomography. J Clin Endocrinol Metab 90(12):6508\u20136515","journal-title":"J Clin Endocrinol Metab"},{"issue":"2","key":"1420_CR30","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1007\/s11914-013-0140-9","volume":"11","author":"AM Cheung","year":"2013","unstructured":"Cheung AM, Adachi JD, Hanley DA, Kendler DL, Davison KS, Josse R, Brown JP, Ste-Marie L-G, Kremer R, Erlandson MC, Dian L, Burghardt AJ, Boyd SK (2013) High-resolution peripheral quantitative computed tomography for the assessment of bone strength and structure: a review by the Canadian Bone Strength Working Group. Curr Osteoporos Rep 11(2):136\u2013146","journal-title":"Curr Osteoporos Rep"},{"issue":"1","key":"1420_CR31","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S8756-3282(98)00159-8","volume":"24","author":"A Laib","year":"1999","unstructured":"Laib A, R\u00fcegsegger P (1999) Calibration of trabecular bone structure measurements of in vivo three-dimensional peripheral quantitative computed tomography with 28-\u03bcm-resolution microcomputed tomography. Bone 24(1):35\u201339","journal-title":"Bone"},{"issue":"5\u20136","key":"1420_CR32","doi-asserted-by":"crossref","first-page":"329","DOI":"10.3233\/THC-1998-65-606","volume":"6","author":"A Laib","year":"1998","unstructured":"Laib A, H\u00e4uselmann HJ, R\u00fcegsegger P (1998) In vivo high resolution 3D-QCT of the human forearm. Technol Health Care 6(5\u20136):329\u2013337","journal-title":"Technol Health Care"},{"issue":"12","key":"1420_CR33","doi-asserted-by":"crossref","first-page":"2558","DOI":"10.1002\/jbmr.157","volume":"25","author":"AJ Burghardt","year":"2010","unstructured":"Burghardt AJ, Kazakia GJ, Sode M, de Papp AE, Link TM, Majumdar S (2010) A longitudinal HR-pQCT study of alendronate treatment in postmenopausal women with low bone density: relations among density, cortical and trabecular microarchitecture, biomechanics, and bone turnover. J Bone Miner Res 25(12):2558\u20132571","journal-title":"J Bone Miner Res"},{"issue":"3","key":"1420_CR34","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1002\/jbmr.3901","volume":"35","author":"N Mikolajewicz","year":"2020","unstructured":"Mikolajewicz N, Bishop N, Burghardt AJ, Folkestad L, Hall A, Kozloff KM, Lukey PT, Molloy-Bland M, Morin SN, Offiah AC, Shapiro J, van Rietbergen B, Wager K, Willie BM, Komarova SV, Glorieux FH (2020) HR-pqct measures of bone microarchitecture predict fracture: systematic review and meta-analysis. J Bone Miner Res 35(3):446\u2013459","journal-title":"J Bone Miner Res"},{"issue":"481","key":"1420_CR35","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1198\/016214507000001373","volume":"103","author":"D Yekutieli","year":"2008","unstructured":"Yekutieli D (2008) Hierarchical false discovery rate-controlling methodology. J Am Stat Assoc 103(481):309\u2013316","journal-title":"J Am Stat Assoc"},{"issue":"9","key":"1420_CR36","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1007\/s00198-020-05438-5","volume":"31","author":"DE Whittier","year":"2020","unstructured":"Whittier DE, Boyd SK, Burghardt AJ, Paccou J, Ghasem-Zadeh A, Chapurlat R, Engelke K, Bouxsein ML (2020) Guidelines for the assessment of bone density and microarchitecture in vivo using high-resolution peripheral quantitative computed tomography. Osteoporos Int 31(9):1607\u20131627","journal-title":"Osteoporos Int"},{"issue":"9","key":"1420_CR37","doi-asserted-by":"crossref","first-page":"2803","DOI":"10.1007\/s00198-016-3612-9","volume":"27","author":"D Gensburger","year":"2016","unstructured":"Gensburger D, Boutroy S, Chapurlat R, Nove-Josserand R, Roche S, Rabilloud M, Durieu I (2016) Reduced bone volumetric density and weak correlation between infection and bone markers in cystic fibrosis adult patients. Osteoporos Int 27(9):2803\u20132813","journal-title":"Osteoporos Int"},{"issue":"8","key":"1420_CR38","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1002\/jbmr.81","volume":"25","author":"E Seeman","year":"2010","unstructured":"Seeman E, Delmas PD, Hanley DA, Sellmeyer D, Cheung AM, Shane E, Kearns A, Thomas T, Boyd SK, Boutroy S, Bogado C, Majumdar S, Fan M, Libanati C, Zanchetta J (2010) Microarchitectural deterioration of cortical and trabecular bone: differing effects of denosumab and alendronate. J Bone Miner Res 25(8):1886\u20131894","journal-title":"J Bone Miner Res"},{"key":"1420_CR39","doi-asserted-by":"crossref","first-page":"349","DOI":"10.2147\/RMHP.S223118","volume":"12","author":"MR Fattahi","year":"2019","unstructured":"Fattahi MR, Niknam R, Shams M, Anushiravani A, Taghavi SA, Omrani GR, Mahmoudi L (2019) The association between prolonged proton pump inhibitors use and bone mineral density. Risk Manag Healthc Policy 12:349\u2013355","journal-title":"Risk Manag Healthc Policy"},{"issue":"9","key":"1420_CR40","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1038\/ajg.2012.200","volume":"107","author":"LE Targownik","year":"2012","unstructured":"Targownik LE, Leslie WD, Davison KS, Goltzman D, Jamal SA, Kreiger N, Josse RG, Kaiser SM, Kovacs CS, Prior JC, Zhou W (2012) The relationship between proton pump inhibitor use and longitudinal change in bone mineral density: a population-based from the canadian multicentre osteoporosis study (CaMos). Am J Gastroenterol 107(9):1361\u20131369","journal-title":"Am J Gastroenterol"},{"issue":"1","key":"1420_CR41","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s00198-018-4788-y","volume":"30","author":"TN Poly","year":"2019","unstructured":"Poly TN, Islam MM, Yang H-C, Wu CC, Li Y-CJ (2019) Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies. Osteoporos Int 30(1):103\u2013114","journal-title":"Osteoporos Int"},{"issue":"3","key":"1420_CR42","doi-asserted-by":"crossref","first-page":"141","DOI":"10.11005\/jbm.2018.25.3.141","volume":"25","author":"Y Nassar","year":"2018","unstructured":"The Korean Society for Bone and Mineral Research, Nassar Y, Richter S (2018) Proton-pump inhibitor use and fracture risk: an updated systematic review and meta-analysis. J Bone Metab 25(3):141\u2013151","journal-title":"J Bone Metab"},{"issue":"2","key":"1420_CR43","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/0021-9290(88)90006-1","volume":"21","author":"JD Currey","year":"1988","unstructured":"Currey JD (1988) The effect of porosity and mineral content on the Young\u2019s modulus of elasticity of compact bone. J Biomech 21(2):131\u2013139","journal-title":"J Biomech"},{"issue":"1","key":"1420_CR44","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/0021-9290(88)90186-8","volume":"21","author":"MB Schaffler","year":"1988","unstructured":"Schaffler MB, Burr DB (1988) Stiffness of compact bone: Effects of porosity and density. J Biomech 21(1):13\u201316","journal-title":"J Biomech"},{"issue":"5","key":"1420_CR45","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1115\/1.2768377","volume":"129","author":"A Ural","year":"2007","unstructured":"Ural A, Vashishth D (2007) Effects of intracortical porosity on fracture toughness in aging human bone: a microCT-based cohesive finite element study. J Biomech Eng 129(5):625\u2013631","journal-title":"J Biomech Eng"},{"issue":"8","key":"1420_CR46","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.2106\/00004623-199308000-00009","volume":"75","author":"RW McCalden","year":"1993","unstructured":"McCalden RW, McGeough JA, Barker MB, Court-Brown CM (1993) Age-related changes in the tensile properties of cortical bone. The relative importance of changes in porosity, mineralization, and microstructure. J Bone Joint Surg Am 75(8):1193\u20131205","journal-title":"J Bone Joint Surg Am"},{"issue":"2","key":"1420_CR47","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/jbmr.3299","volume":"33","author":"E Biver","year":"2018","unstructured":"Biver E, Durosier-Izart C, Chevalley T, van Rietbergen B, Rizzoli R, Ferrari S (2018) Evaluation of radius microstructure and areal bone mineral density improves fracture prediction in postmenopausal women. J Bone Miner Res 33(2):328\u2013337","journal-title":"J Bone Miner Res"},{"issue":"Suppl 2","key":"1420_CR48","doi-asserted-by":"crossref","first-page":"S11","DOI":"10.1016\/S0020-1383(16)47003-8","volume":"47","author":"G Osterhoff","year":"2016","unstructured":"Osterhoff G, Morgan EF, Shefelbine SJ, Karim L, McNamara LM, Augat P (2016) Bone mechanical properties and changes with osteoporosis. Injury 47(Suppl 2):S11-20","journal-title":"Injury"},{"issue":"5","key":"1420_CR49","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/S8756-3282(97)00173-7","volume":"21","author":"YN Yeni","year":"1997","unstructured":"Yeni YN, Brown CU, Wang Z, Norman TL (1997) The influence of bone morphology on fracture toughness of the human femur and tibia. Bone 21(5):453\u2013459","journal-title":"Bone"},{"issue":"12","key":"1420_CR50","doi-asserted-by":"crossref","first-page":"3135","DOI":"10.1016\/j.jbiomech.2014.06.022","volume":"47","author":"TL Turnbull","year":"2014","unstructured":"Turnbull TL, Baumann AP, Roeder RK (2014) Fatigue microcracks that initiate fracture are located near elevated intracortical porosity but not elevated mineralization. J Biomech 47(12):3135\u20133142","journal-title":"J Biomech"},{"issue":"1","key":"1420_CR51","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1002\/jbmr.171","volume":"26","author":"HM Macdonald","year":"2011","unstructured":"Macdonald HM, Nishiyama KK, Kang J, Hanley DA, Boyd SK (2011) Age-related patterns of trabecular and cortical bone loss differ between sexes and skeletal sites: a population-based HR-pQCT study. J Bone Miner Res 26(1):50\u201362","journal-title":"J Bone Miner Res"},{"issue":"8","key":"1420_CR52","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1007\/s00198-014-2719-0","volume":"25","author":"CE Kawalilak","year":"2014","unstructured":"Kawalilak CE, Johnston JD, Olszynski WP, Kontulainen SA (2014) Characterizing microarchitectural changes at the distal radius and tibia in postmenopausal women using HR-pQCT. Osteoporos Int 25(8):2057\u20132066","journal-title":"Osteoporos Int"},{"issue":"6","key":"1420_CR53","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1089\/bfm.2016.0204","volume":"12","author":"J Teerapornpuntakit","year":"2017","unstructured":"Teerapornpuntakit J, Chanprapaph P, Karoonuthaisiri N, Charoenphandhu N (2017) Site-specific onset of low bone density and correlation of bone turnover markers in exclusive breastfeeding mothers. Breastfeed Med 12(6):331\u2013337","journal-title":"Breastfeed Med"},{"issue":"4","key":"1420_CR54","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1053\/j.ajkd.2019.07.012","volume":"75","author":"Z Al-Aly","year":"2020","unstructured":"Al-Aly Z, Maddukuri G, Xie Y (2020) Proton pump inhibitors and the kidney: implications of current evidence for clinical practice and when and how to deprescribe. Am J Kidney Dis 75(4):497\u2013507","journal-title":"Am J Kidney Dis"},{"issue":"4","key":"1420_CR55","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/ki.2014.74","volume":"86","author":"M-L Blank","year":"2014","unstructured":"Blank M-L, Parkin L, Paul C, Herbison P (2014) A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. Kidney Int 86(4):837\u2013844","journal-title":"Kidney Int"},{"issue":"2","key":"1420_CR56","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1093\/ndt\/gfw470","volume":"33","author":"S Nochaiwong","year":"2018","unstructured":"Nochaiwong S, Ruengorn C, Awiphan R, Koyratkoson K, Chaisai C, Noppakun K, Chongruksut W, Thavorn K (2018) The association between proton pump inhibitor use and the risk of adverse kidney outcomes: a systematic review and meta-analysis. Nephrol Dial Transplant 33(2):331\u2013342","journal-title":"Nephrol Dial Transplant"},{"issue":"3","key":"1420_CR57","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1053\/j.gastro.2017.05.046","volume":"153","author":"DCF Klatte","year":"2017","unstructured":"Klatte DCF, Gasparini A, Xu H, de Deco P, Trevisan M, Johansson ALV, Wettermark B, \u00c4rnl\u00f6v J, Janmaat CJ, Lindholm B, Dekker FW, Coresh J, Grams ME, Carrero JJ (2017) Association between proton pump inhibitor use and risk of progression of chronic kidney disease. Gastroenterology 153(3):702\u2013710","journal-title":"Gastroenterology"},{"issue":"10","key":"1420_CR58","doi-asserted-by":"crossref","first-page":"e0204231","DOI":"10.1371\/journal.pone.0204231","volume":"13","author":"A Rodr\u00edguez-Poncelas","year":"2018","unstructured":"Rodr\u00edguez-Poncelas A, Barcel\u00f3 MA, Saez M, Coll-de-Tuero G (2018) Duration and dosing of proton pump inhibitors associated with high incidence of chronic kidney disease in population-based cohort. PLoS ONE 13(10):e0204231","journal-title":"PLoS ONE"},{"issue":"5","key":"1420_CR59","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1007\/s12325-023-02481-6","volume":"40","author":"JM LaForge","year":"2023","unstructured":"LaForge JM, Urso K, Day JM, Bourgeois CW, Ross MM, Ahmadzadeh S, Shekoohi S, Cornett EM, Kaye AM, Kaye AD (2023) Non-steroidal anti-inflammatory drugs: clinical implications, renal impairment risks, and AKI. Adv Ther 40(5):2082\u20132096","journal-title":"Adv Ther"},{"issue":"1","key":"1420_CR60","doi-asserted-by":"crossref","first-page":"10165","DOI":"10.1038\/s41598-021-89442-7","volume":"11","author":"T Waas","year":"2021","unstructured":"Waas T, Schulz A, Lotz J, Rossmann H, Pfeiffer N, Beutel ME, Schmidtmann I, M\u00fcnzel T, Wild PS, Lackner KJ (2021) Distribution of estimated glomerular filtration rate and determinants of its age dependent loss in a German population-based study. Sci Rep 11(1):10165","journal-title":"Sci Rep"},{"issue":"5","key":"1420_CR61","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1136\/gutjnl-2015-310376","volume":"65","author":"F Imhann","year":"2016","unstructured":"Imhann F, Bonder MJ, Vich Vila A, Fu J, Mujagic Z, Vork L, Tigchelaar EF, Jankipersadsing SA, Cenit MC, Harmsen HJM, Dijkstra G, Franke L, Xavier RJ, Jonkers D, Wijmenga C, Weersma RK, Zhernakova A (2016) Proton pump inhibitors affect the gut microbiome. Gut 65(5):740\u2013748","journal-title":"Gut"},{"issue":"6","key":"1420_CR62","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1002\/jbmr.3114","volume":"32","author":"JD Guss","year":"2017","unstructured":"Guss JD, Horsfield MW, Fontenele FF, Sandoval TN, Luna M, Apoorva F, Lima SF, Bicalho RC, Singh A, Ley RE, van der Meulen MC, Goldring SR, Hernandez CJ (2017) Alterations to the gut microbiome impair bone strength and tissue material properties. J Bone Miner Res 32(6):1343\u20131353","journal-title":"J Bone Miner Res"},{"issue":"13","key":"1420_CR63","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.2147\/CIA.S169223","volume":"30","author":"M Parvaneh","year":"2018","unstructured":"Parvaneh M, Karimi G, Jamaluddin R, Ng MH, Zuriati I, Muhammad SI (2018) Lactobacillus helveticus (ATCC 27558) upregulates Runx2 and Bmp2 and modulates bone mineral density in ovariectomy-induced bone loss rats. Clin Interv Aging 30(13):1555\u20131564","journal-title":"Clin Interv Aging"},{"issue":"12","key":"1420_CR64","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1093\/rheumatology\/kez302","volume":"58","author":"M Das","year":"2019","unstructured":"Das M, Cronin O, Keohane DM, Cormac EM, Nugent H, Nugent M, Molloy C, O\u2019Toole PW, Shanahan F, Molloy MG, Jeffery IB (2019) Gut microbiota alterations associated with reduced bone mineral density in older adults. Rheumatology 58(12):2295\u20132304","journal-title":"Rheumatology"},{"issue":"5","key":"1420_CR65","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1007\/s00198-019-04855-5","volume":"30","author":"C Li","year":"2019","unstructured":"Li C, Huang Q, Yang R, Dai Y, Zeng Y, Tao L, Li X, Zeng J, Wang Q (2019) Gut microbiota composition and bone mineral loss\u2014epidemiologic evidence from individuals in Wuhan. China Osteoporos Int 30(5):1003\u20131013","journal-title":"China Osteoporos Int"},{"key":"1420_CR66","doi-asserted-by":"crossref","unstructured":"Thong BKS, Ima-Nirwana S, Chin K-Y. Proton Pump Inhibitors and Fracture Risk: A Review of Current Evidence and Mechanisms Involved. Int J Environ Res Public Health [Internet]. 2019 [cited 2020 Sep 20];16(9). https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC6540255\/","DOI":"10.3390\/ijerph16091571"},{"issue":"7","key":"1420_CR67","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/j.amjmed.2005.02.007","volume":"118","author":"MB O\u2019Connell","year":"2005","unstructured":"O\u2019Connell MB, Madden DM, Murray AM, Heaney RP, Kerzner LJ (2005) Effects of proton pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med 118(7):778\u2013781","journal-title":"Am J Med"},{"issue":"6","key":"1420_CR68","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/nm.1963","volume":"15","author":"T Schinke","year":"2009","unstructured":"Schinke T, Schilling AF, Baranowsky A, Seitz S, Marshall RP, Linn T, Blaeker M, Huebner AK, Schulz A, Simon R, Gebauer M, Priemel M, Kornak U, Perkovic S, Barvencik F, Beil FT, Del Fattore A, Frattini A, Streichert T, Pueschel K, Villa A, Debatin K-M, Rueger JM, Teti A, Zustin J, Sauter G, Amling M (2009) Impaired gastric acidification negatively affects calcium homeostasis and bone mass. Nat Med 15(6):674\u2013681","journal-title":"Nat Med"},{"issue":"12","key":"1420_CR69","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1359\/jbmr.1998.13.12.1924","volume":"13","author":"DJ Morton","year":"1998","unstructured":"Morton DJ, Barrett-Connor EL, Schneider DL (1998) Nonsteroidal anti-inflammatory drugs and bone mineral density in older women: the Rancho Bernardo study. J Bone Miner Res 13(12):1924\u20131931","journal-title":"J Bone Miner Res"},{"issue":"1","key":"1420_CR70","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1002\/jbmr.5650110106","volume":"11","author":"DC Bauer","year":"1996","unstructured":"Bauer DC, Orwoll ES, Fox KM, Vogt TM, Lane NE, Hochberg MC, Stone K, Nevitt MC, Study of Osteoporotic Fractures Research Group (1996) Aspirin and NSAID use in older women: effect on bone mineral density and fracture risk. J Bone Miner Res 11(1):29\u201335","journal-title":"J Bone Miner Res"},{"issue":"10","key":"1420_CR71","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1359\/jbmr.2003.18.10.1795","volume":"18","author":"LD Carbone","year":"2003","unstructured":"Carbone LD, Tylavsky FA, Cauley JA, Harris TB, Lang TF, Bauer DC, Barrow KD, Kritchevsky SB (2003) Association between bone mineral density and the use of nonsteroidal anti-inflammatory drugs and aspirin: impact of cyclooxygenase selectivity. J Bone Miner Res 18(10):1795\u20131802","journal-title":"J Bone Miner Res"},{"issue":"4","key":"1420_CR72","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1007\/s00198-011-1692-0","volume":"23","author":"P Vestergaard","year":"2012","unstructured":"Vestergaard P, Hermann P, Jensen J-EB, Eiken P, Mosekilde L (2012) Effects of paracetamol, non-steroidal anti-inflammatory drugs, acetylsalicylic acid, and opioids on bone mineral density and risk of fracture: results of the Danish Osteoporosis Prevention Study (DOPS). Osteoporos Int 23(4):1255\u20131265","journal-title":"Osteoporos Int"},{"issue":"5","key":"1420_CR73","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1016\/j.jbiomech.2014.12.024","volume":"48","author":"B van Rietbergen","year":"2015","unstructured":"van Rietbergen B, Ito K (2015) A survey of micro-finite element analysis for clinical assessment of bone strength: the first decade. J Biomech 48(5):832\u2013841","journal-title":"J Biomech"},{"issue":"1","key":"1420_CR74","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","volume":"57","author":"Y Benjamini","year":"1995","unstructured":"Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol 57(1):289\u2013300","journal-title":"J R Stat Soc Series B Stat Methodol"},{"issue":"8","key":"1420_CR75","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1002\/jbmr.1916","volume":"28","author":"TL Nickolas","year":"2013","unstructured":"Nickolas TL, Stein EM, Dworakowski E, Nishiyama KK, Komandah-Kosseh M, Zhang CA, McMahon DJ, Liu XS, Boutroy S, Cremers S, Shane E (2013) Rapid cortical bone loss in patients with chronic kidney disease. J Bone Miner Res 28(8):1811\u20131820","journal-title":"J Bone Miner Res"}],"container-title":["Calcified Tissue International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00223-025-01420-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00223-025-01420-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00223-025-01420-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T13:21:17Z","timestamp":1766755277000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00223-025-01420-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,22]]},"references-count":75,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["1420"],"URL":"https:\/\/doi.org\/10.1007\/s00223-025-01420-7","relation":{},"ISSN":["1432-0827"],"issn-type":[{"value":"1432-0827","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,22]]},"assertion":[{"value":"8 October 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 October 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All authors besides BvR\u00a0declare that they do not have any conflicts of interests BvR is a consultant for Scanco Medical AG and has received grant support from Amolyt Pharma and Avania.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosures"}},{"value":"Ethical Approval No. STZ 20\/07, granted by ethical committee of the Canton of Zurich. Ethical Approval No. BASEC 2019-01790 granted by the Swiss Association of Research Ethics Committees.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"No animals were harmed in this study. The study was approved by the Ethics Committee of the Canton Z\u00fcrich and the Swiss Agency for Therapeutic Products, and written informed content was given by all study participants prior to enrolment.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and Animal Rights and Informed Consent"}},{"value":"Available.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participations"}},{"value":"Available and included in general consent that all participants signed prior to participation.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publications"}}],"article-number":"131"}}