High osteoprotegerin is associated with development of foot ulcer in type 1 diabetes

Abstract

Background and aim: 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.

Materials and methods: 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.

Results: 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, HbA_1c, 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).

Conclusion: Higher osteoprotegerin levels were associated with development of foot ulcer, even after comprehensive adjustment.

Keywords: Amputation; Charcot foot; Diabetic complications; Foot ulcer; Osteoprotegerin; Type 1 diabetes.