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 (eGFRcys) is superior in predicting hip fracture risk to eGFR based on creatinine (eGFRcr) or the combination (eGFRcr-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 eGFRcys, eGFRcr, and eGFRcr-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 eGFRcys 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 eGFRcys (but not lower eGFRcr or lower eGFRcr-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 eGFRcys, eGFRcr, and eGFRcr-cys, respectively. Similarly, after adjustment for age, race, site, and body mass index, eGFR < 60 mL/min/1.73 m2 defined by eGFRcys, but not eGFRcr or eGFRcr-cys, was associated with higher hip fracture risk. The association between eGFRcys 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 eGFRcys have an increased risk of hip fracture that is explained in large part by greater burden of risk factors among men with lower eGFRcys. In contrast, lower eGFRcr or lower eGFRcr-cys was not associated with a higher age-adjusted hip fracture risk. 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 (eGFRcys) is superior in predicting hip fracture risk to eGFR based on creatinine (eGFRcr) or the combination (eGFRcr-cys) also is uncertain. Nested case-cohort. 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). eGFRcys, eGFRcr, and eGFRcr-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). Incident hip fracture ascertained by participant contacts every 4 months and confirmed with radiographic reports. Median eGFRcys 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 eGFRcys (but not lower eGFRcr or lower eGFRcr-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 eGFRcys, eGFRcr, and eGFRcr-cys, respectively. Similarly, after adjustment for age, race, site, and body mass index, eGFR < 60 mL/min/1.73 m2 defined by eGFRcys, but not eGFRcr or eGFRcr-cys, was associated with higher hip fracture risk. The association between eGFRcys 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. Findings not generalizable to other populations; residual confounding may exist. Older community-dwelling men with lower eGFRcys have an increased risk of hip fracture that is explained in large part by greater burden of risk factors among men with lower eGFRcys. In contrast, lower eGFRcr or lower eGFRcr-cys was not associated with a higher age-adjusted hip fracture risk.