title: High osteoprotegerin is associated with development of foot ulcer in type 1 diabetes.
abstract: The bone-related peptide osteoprotegerin has been linked to vascular calcification and peripheral vascular disease. We investigated the association between osteoprotegerin and development of foot complications in persons with type 1 diabetes.
  
  
  
  Prospective observational study of 573 persons with type 1 diabetes, 225 women; age [mean±SD] 42.3±10.3years. Plasma osteoprotegerin was measured by ELISA.
  
  
  
  Median (IQR) osteoprotegerin was 2.80(2.35-3.63)μg/L and follow-up time (median (range)) was 12.7(0.1-15.6)years. Endpoints included: new foot ulceration (n=153), Charcot foot (n=14), vascular surgery/amputation (n=53), loss of foot pulse (n=57), and peripheral neuropathy (n=99). In unadjusted analyses, higher osteoprotegerin was associated with development of all endpoints (p≤0.026). Higher osteoprotegerin remained associated with development of foot ulcer, and the combination of vascular surgery/amputation, loss of foot pulse and neuropathy (p≤0.001) in a sex and age adjusted model. After further adjustment (nephropathy status, smoking, HbA1c, systolic blood pressure, serum cholesterol, high sensitivity C-reactive protein, eGFR, and presence of neuropathy and/or claudication and/or foot ulcer at baseline), higher osteoprotegerin remained associated with development of foot ulcer (HR (95% CI) per doubling: 1.75 (1.04-2.97); p=0.037).
  
  
  
  Higher osteoprotegerin levels were associated with development of foot ulcer, even after comprehensive adjustment.
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark. Electronic address: ehnp@steno.dk.
authors.forename: Emilie H
authors.initials: EH
authors.lastname: Zobel
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Bernt J
authors.initials: BJ
authors.lastname: von Scholten
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Lajer
authors.affiliation: Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Jorsal
authors.affiliation: Department of Clinical Research, Nordsjællands Hospital, University of Copenhagen, Hillerød, Denmark; Health, Aarhus University, Aarhus, Denmark.
authors.forename: Lise
authors.initials: L
authors.lastname: Tarnow
authors.affiliation: Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark; Center for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital, Odense, Denmark.
authors.forename: Lars M
authors.initials: LM
authors.lastname: Rasmussen
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark; Department of Dermato-venerology and Copenhagen Wound Healing Center, Bispebjerg Hospital, University Hospital of Copenhagen, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Holstein
authors.affiliation: Department of Medical Endocrinology, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Parving
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: T W
authors.initials: TW
authors.lastname: Hansen
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark; Health, Aarhus University, Aarhus, Denmark; Novo Nordisk Foundation Center for Metabolic Research, Copenhagen, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Rossing
mesh_terms: D000328:Adult; D000671:Amputation, Surgical; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D017719:Diabetic Foot / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D053244:Osteoprotegerin / Q000097:blood*; D011446:Prospective Studies
chemical_list: D053244:Osteoprotegerin; C506030:TNFRSF11B protein, human
keywords: Amputation; Charcot foot; Diabetic complications; Foot ulcer; Osteoprotegerin; Type 1 diabetes