Serum phosphate is associated with increased risk of bone fragility fractures in haemodialysis patients
Authors: Barrera-Baena Pedro , Rodríguez-García Minerva , Rodríguez-Rubio Enrique , González-Llorente Lucía , Ortiz Alberto , Zoccali Carmine , Locatelli Francesco , Floege Jürgen , Cohen-Solal Martine , Ferreira Manuel Aníbal , Ketteler Markus , London Gerard Michel , Gorriz-Teruel José Luis , Sánchez-Álvarez Emilio , Hevia-Suárez Miguel Ángel , Fernández-Gómez Jesús María , Martín-Carro Beatriz , Gómez-Alonso Carlos , Alonso-Montes Cristina , Cannata-Andía Jorge Benito , Fernández-Martín José Luis ,   COSMOS, Marosi Leo , Krankenhaus A Ö , Robl Bernhard , Kiss Heinrich , Neyer Ulrich , Jilly Wilfried , Kramar  , Verbeelen Dierik , Wauters Anne , Cuvelier René , De Mouscron C M , Dratwa Max , Brugmann Chu , Tielemans Christian , Dehout François , Claus Pierre , Dhondt A M , Jeren-Strujic Branka , Gulin Marijana , Coric-Martinovic Valentina , Pavlovic Drasko , Smrzova Jana , Pavlikova  , Valkovsky  , Zahradnik  , Teplan Vladimir , Pavukova  , Poliklinikou Nemocnice , Stredisko Dialyzacni , Nemocnice Moucka , Otte Overlæge Kjeld , Sygehus Fredericia , Heaf James , Danielsen Overlæge Henning , Sygehus Viborg , Kolunen Mari , Asola L L Markku , Jean-Baptiste Philit , Nicoud Philippe , Maurice François-Louis , Bounab Mohamed Brahim , Bertocchio Philippe , Jean Guillaume , Chantal Bony , Grimal Pierre , Gaultier Jacques , Mouneimne Alex , Brignon  , Dupuy  , Jaulin Jean-Paul , Urena Pablo , Pocheville Marc , Masson Valérie , Uzan Marc , Besnier Dominique , Labeeuw Michel , Glowacki  , Cattanéo  , Guillaume Bois , Didier Ducloux , Bouchouareb  , Philippe Petitjean , Djamel Dahmane , Kim-Seng A N G , Saveanu  , London Gerard , Boussad Bouali , Wambergue François-Pascal , De Fremont J F , Michel  , Giraud Patrick , Eche Jean-Paul , Lopez Bernard , Delcroix Catherine , Duchet  , Majdalani Ghandour , Guy  , Hadj  , Guillodo Marie-Paule , Selbach Jochen , Röckel Arnold , Krumme Bernd , Bolley  , Grieger M , Hahn W , Daschner M , Iwig B , Arendt Susanne , Berger Dieter , Wölbert Bernd , Holzmann  , Graf Guenther , Brockmann Carsten , Brech Wolfgang , Mandelbaum Alexander , Lauerwald Wolfang , Bunia J , Lammer Ulrich , Au Diep Thanh , Kurth Carsten , Schnierda  , Stolz  , Harlos J , Berweck S , Brensing Karl-August , Brensing Karl-August , Kreft B , Jahnz Heinrich , Kohnle Wolfgang , Kamen Wilfried , Sodemann  , Nachtigall Peter , Schäffer Jürgen , Leimenstoll  , Stenger Karl-Otmar , Wollschläger  , Langer Christine , Clasen Wolfgang , Röger Christoph , Burkhardt Klaus , Steinbach Jutta , Schulz Walter , Pommer Wolfgang , Wilfling Michael , Schmaltz Karla , Eichhorn Michael , Oser Bertil , Müller Eckhard , Striebing Carola , Schobel Hans-Paul , Ludwig Wolfgang , Frei Ulrich , Becker Helmut Peter , Fischer Hans-Christoph , Goller Maximilian , Brückner Dieter , Janning Gottfried , Bagnewski Wolfgang , Preßler Horst , Haufe Christoph , Grützmacher Peter , Miska Hans-Joachim , Lenz Tomas , Hoeft Olaf Frank , Krause Rolfdieter , de Groot Kirsten , Armbruster Helmut , Spellerberg Peter , Stützer Wolfgang , Nikolay Josef , Schmidt Rüdiger , Mann J , Roth Rainer , Lüth Johann-Borwin , Merscher Sybille , Schmidt-Gürtler Hans-Jürgen , Gross Wolfgang , Dehnert  , Roth  , Floege Jürgen , Ketteler Markus , Heidenreich Stefan , Bahlmann Günter , Loke Olaf , Becker Matthias , Ebbinghaus Rolf , Weiß Matthias , Frye Berhard , Matzkies Fritz , Gebauer Katrin , Schurek H-J , Heck Markus , Hohage Helge , Welling Ullrich , Zeh Matthias , Schwietzer  , Haller Hermann , Selbach Jochen , Metz-Kurschel Ulrike , Fulde Roland , Ganzemüller Christoph , Radermacher Jörg , Materna Joachim , Hebgen Oliver , Weber Bernhard , Hummel Dieter , Scheuerle  , Kierdorf Horst , Kierdorf Horst , Beige Joachim , Lorenz R , Plakias Dimitrios , Solomakou Stauroula , Bristogiannis Georgios , Kalaitzidis Kleonikos , Kavvadias Dimitrios , Memmos Dimitrios , Papantoniou Antonis , Stamatelou Kyriaki , Stefanidis Ioannis , Siamopoulos Konstantinos , Rikker Csaba , Kulcsár Imre , Tichy Béla , Ferenczi Sandor , Hering Andrea , Árkossy Ottó , Nagy Judit , de Gregorio Ascanio , Frattini Gianmaria , La Corte Antonio , Rotolo Ugo , Brancaccio Diego , Gallieni Maurizio , Fusaro  , Albertazzi Alberto , Nazzaro Livia , Randazzo Francesco , Locatelli Francesco , Lodeserto Cosimo , D'Angelo Angela , Frascà Giovanni Maria , Malberti Fabio , Procaccini Deni Aldo , Dell Cesare , Del Rosso Goffredo , Dialisi E , Donatella Spotti , Bianchi Giuseppe , Biagini Marco , Aucella Filippo , Scarlatella Antonio , Jeantet A , Dialisi E , Farina Marco , Francesco Canulla , Cossu Maria , Meneghel Ssa Gina , Bonomini Mario , Palla Roberto , Massimo Morosetti , Marinangeli Giancarlo , Estivi Rosella , Giuliano Martin , Orsola-Malpighi Antonio Santoro Md Poloclinico S , Scanziani Renzo , Ferruccio Conte , Munatetto Giorgio , Giordano Pastori , Rossi Giacomino , Cagnoli Leonardo , Cagnoli Leonardo , Morossetti Massimo , Plutino D , Galbiati Alberto , Gesualdo Loreto , Querques Mario , Colussi Giacomo , Nefrologia U O , Ospedale di Circolo e Fondazione Macchi A O , Tommasi Adalberto , Van Bommel E F H , Bos Willem-Jan , Verseput G H , Vleming L , De Hoek C T Op , Van Hamersvelt H W , Hoekstra F , Kaasjager H A H , Durlik Magdalena , Grzeszczyk Miroslav , Rydzewski Andrzej , Sliwicka Dorota , Sydor Antoni , Gauda Tadeusz , Figarska Malgorzata , Powiatowy Szpital , StacjaDializ  , Trudnowski Slawomir , Matulewicz-Gilewicz Med Justyna , Sobocki Marek , Felisiak Jacek J , Rutkowski Boleslaw , Rudka Roman , Bidas Kizysztof , Krzywicki Pawel , Hawryluk Jaroslaw , Gozdzik Zdzislaw , Nefrologii Oddzial , Dziewanowski Krzysztof , Resina Cristina , Carrera Fernando , Maia Pedro Afonso Coelho , Cruz Joao , Ferreira Aníbal , Rocha Ernesto , Alves Doutor Rui , Fernandes João Carlos , Ponce Pedro Magalhaes , Travassos Joao Paulo , Ribeiro Sílvia , Rodrigues Ilídio , Macavei Radu , Covic Adrian , Bako Cristian Gabriel , Alecsandru Radu , Ghenu Adrian , Golea Ovidiu-Sorin , Craciun Irinel , Iacob Ioana , Kralj-Lopert Simona , Malovrh Marko , Benedik Mihael , Ortiz Milagros , Rubio Ester , Rentero Ramon , Amigo Soler , Mas Enrique Ajenjo , Gutiérrez Josep Prim , Herrero Guillermina Fernández , Josefade la Torre Diz Mª , Seguí Rafael Giner , González Juan Navarro , Megido  , Guervas Carlos Santiago , Roldan Carmina Gomez , Otegui Fernando Vidaur , Reyes Guillermo Martín , de Paula de Pedro Antonio , Pérez Pilar Sánchez , López Margarita , Soler Mª Carmen Prados , Gorriz José Luis , Calvo Maria Dolores Paz , Burgos Rafael Romero , Rosaleda La , Rodrigo Mateos Pedro C , Jimenez Dolores Arenas , Sanz Aurelio , Rogland Björn , Karsberg Margareta , Gutierrez Alberto , Bucht Stig , Burnier Michel , Martin Pierre-Yves , Thomas Kistler , Marone Claudio , Wüthrich Rudolf , Mcclelland Peter , Smithard D , Erekosima Ibi , Goldsmith David , Mark Thomas , Wilkie Martin , Cassidy Mike , Wood Morwenna , Naik Ramesh , Harnett Patrick , Will Es , Newstead Charles 
Published: September 2023

ABSTRACT

Background
Bone fragility fractures are associated with high morbidity and mortality. This study analysed the association between the current biochemical parameters of chronic kidney disease–mineral and bone disorders (CKD-MBD) and bone fragility fractures in the COSMOS (Current management Of Secondary hyperparathyroidism: a Multicentre Observational Study) project.

Methods
COSMOS is a 3-year, multicentre, open cohort, prospective, observational study carried out in 6797 haemodialysis patients (227 centres from 20 European countries). The association of bone fragility fractures (outcome) with serum calcium, phosphate and parathyroid hormone (PTH) (exposure), was assessed using standard Cox proportional hazards regression and Cox proportional hazards regression for recurrent events. Additional analyses were performed considering all-cause mortality as a competitive event for bone fragility fracture occurrence. Multivariable models were used in all strategies, with the fully adjusted model including a total of 24 variables.

Results
During a median follow-up of 24 months, 252 (4%) patients experienced at least one bone fragility fracture (incident bone fragility fracture rate 28.5 per 1000 patient-years). In the fractured and non-fractured patients, the percentage of men was 43.7% and 61.4%, mean age 68.1 and 63.8 years and a haemodialysis vintage of 55.9 and 38.3 months, respectively. Baseline serum phosphate &gt;6.1 mg/dL (reference value 4.3–6.1 mg/dL) was significantly associated with a higher bone fragility fracture risk in both regression models {hazard ratio (HR) 1.53 [95% confidence interval (CI) 1.10–2.13] and HR 1.44 (95% CI 1.02–2.05)}. The significant association persisted after competitive risk analysis [subHR 1.42 (95% CI 1.02–1.98)] but the finding was not confirmed when serum phosphate was considered as a continuous variable. Baseline serum calcium showed no association with bone fragility fracture risk in any regression model. Baseline serum PTH &gt;800 pg/mL was significantly associated with a higher bone fragility fracture risk in both regression models, but the association disappeared after a competitive risk analysis.

Conclusions
Hyperphosphatemia was independently and consistently associated with an increased bone fracture risk, suggesting serum phosphate could be a novel risk factor for bone fractures in haemodialysis patients.