Estimated GFR and risk of hip fracture in older men: Comparison of associations using cystatin C and creatinine

Background Higher serum cystatin C level is associated with an increased risk of hip fracture in postmenopausal white women, but there is a paucity of data for men. Whether estimated glomerular filtration rate (eGFR) based on cystatin C (eGFR_cys) is superior in predicting hip fracture risk to eGFR based on creatinine (eGFR_cr) or the combination (eGFR _cr-cys) also is uncertain. Study Design Nested case-cohort. Setting & Participants Participants enrolled in the Osteoporotic Fractures in Men (MrOS) Study (5,994 men aged ≥65 years from 6 US centers) including a random subcohort of 1,602 men and 168 men with incident hip fractures (51 of whom were in the subcohort). Predictor eGFR_cys, eGFR_cr, and eGFR_cr-cys computed using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations and expressed in categories of <60, 60-74, and ≥75 mL/min/1.73 m² (referent group). Outcome Incident hip fracture ascertained by participant contacts every 4 months and confirmed with radiographic reports. Results Median eGFR_cys was 72.9 (IQR, 60.5-85.7) mL/min/1.73 m². In unadjusted models, all measures of eGFR were associated with increased hip fracture risk. However, after adjustment for age, race, site, and body mass index, the association of lower eGFR _cys (but not lower eGFR_cr or lower eGFR_cr-cys) with higher hip fracture risk remained: for <60 versus ≥75 mL/min/1.73 m², HRs were 1.96 [95% CI, 1.25-3.09], 0.84 [95% CI, 0.52-1.37], and 1.08 [95% CI, 0.66-1.77] for eGFR_cys, eGFR_cr, and eGFR_cr-cys, respectively. Similarly, after adjustment for age, race, site, and body mass index, eGFR < 60 mL/min/1.73 m² defined by eGFR_cys, but not eGFR_cr or eGFR_cr-cys, was associated with higher hip fracture risk. The association between eGFR _cys and hip fracture was not explained by levels of calciotropic hormones or inflammatory markers, but the relationship was attenuated and no longer reached significance (for <60 vs ≥75 mL/min/1.73 m²: HR, 1.43; 95% CI, 0.88-2.34) after consideration of additional clinical risk factors and bone mineral density. Limitations Findings not generalizable to other populations; residual confounding may exist. Conclusions Older community-dwelling men with lower eGFR_cys have an increased risk of hip fracture that is explained in large part by greater burden of risk factors among men with lower eGFR_cys. In contrast, lower eGFR_cr or lower eGFR_cr-cys was not associated with a higher age-adjusted hip fracture risk.