Low Plasma Level of Leucine-Rich Repeat-Containing 17 (LRRc17) Is an Independent and Additive Risk Factor for Osteoporotic Fractures in Postmenopausal Women

A novel role of leucine-rich repeat-containing 17 (LRRc17), an LRR protein secreted by osteoblasts, as a negative regulator of receptor activator of NF-κB ligand–induced osteoclast differentiation was found. However, the clinical association between LRRc17 and osteoporotic fracture (OF) has not yet been investigated. We hypothesized that low circulating plasma level of LRRc17 might serve as an independent and additive risk factor for OF, including vertebral fractures (VF) and non-vertebral fractures (non-VF). In this case-control study, 102 OF cases and 102 age- and body mass index–matched controls (mean age, 63.2 years) were analyzed among 532 postmenopausal women. VF (n = 49) and non-VF (n = 60) participants were identified using lateral thoracolumbar radiographs and an interviewer-assisted questionnaire, respectively. Median LRRc17 levels were significantly lower in participants with any OF (117.5 versus 197.3 pg/mL, p < 0.001), VF (93.2 versus 172.4 pg/mL, p = 0.002), and non-VF (124.5 versus 206.9 pg/mL, p = 0.008) compared with the respective controls without fractures. The prevalence of OF increased from the highest LRRc17 tertile (≥228.5 pg/mL, 33.8%) to the lowest (<95.6 pg/mL, 63.2%). Each log unit decrease of LRRc17 was associated with greater risk of OF (odds ratio [OR] = 1.46; 95% confidence interval [CI] 1.10–1.96; p = 0.009) and VF (OR = 2.42; 95% CI 1.39–4.23; p = 0.002). Plasma LRRc17 significantly improved discrimination of OF, particularly VF, when added to models including clinical risk factors and bone mineral density according to the area under receiver operating characteristics curves (AUC 0.71 to 0.81, p = 0.036), category-free net reclassification improvement (0.79; 95% CI 0.37–1.21; p < 0.001), and integrated discrimination improvement (0.13; 95% CI 0.06–0.20; p < 0.001). Low plasma LRRc17 was an independent risk factor for OF, which improved risk stratification, particularly in the spines of postmenopausal women.