CXCL9 Predicts the Risk of Osteoporotic Hip Fracture in a Prospective Cohort of Chinese Men—A Matched Case–Control Study

Abstract

Recent experimental work has identified CXCL9 as a promoter for the differentiation of osteoclast progenitors into osteoclasts, with resultant bone resorption. However, no human study has validated an association between this chemokine and osteoporosis or fracture risk. We conducted a matched case-control study nested in the prospective, population-based Singapore Chinese Health Study. Fifty-five men and 119 women with incident hip fractures, occurring median 6.2 years after blood collection, were matched individually to controls by age at recruitment, sex, and duration of blood storage. Serum chemokines, CXCL9 and CXCL10, were measured using immunoassays. Multivariable conditional logistic regression models that included age at blood collection, body mass index, smoking, and diabetes as covariates were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for association with hip fracture risk. Predictive utility of chemokine for hip fracture risk was examined by comparing area under receiver operating characteristic curves (AUC) between prognostic models with and without the chemokine. Increasing CXCL9 levels were associated with increasing hip fracture risk in men but not in women (p interaction = 0.002); comparing extreme quartiles, the OR (95% CI) in the highest quartile was 10. 35 (1.90-56.39) in men (p trend = 0.002) but 1.46 (0.59-3.60) in women (p trend = 0.32). Adding CXCL9 to a prognostic model that already incorporated age and other risk factors improved the AUC (95% CI) from 0.65 (0.55-0.76) to 0.74 (0.65-0.83) for the predictive utility of hip fractures in men but not in women. Conversely, the association between CXCL10 and hip fracture risk was not statistically significant in either sex.

Effects of circulating inflammatory proteins on osteoporosis and fractures: evidence from genetic correlation and Mendelian randomization study

“…In addition, bone erosion was prevented by vitamin D supplementation that inhibited the CXCL10 pathway ( 44 ). It has also been shown that there is no significant correlation between CXCL10 and hip fracture risk ( 45 ). Our MR analysis revealed that genetically predicted CXCL10 can promote fracture occurrence.…”

Association between Circulating Levels of CXCL9 and CXCL10 and Physical Frailty in Older Adults

“…Data from a nested case-control study of 174 cases and 174 controls during a median follow-up of 6.2 years showed that CXCL9 levels, but not CXCL10 levels, were associated with the risk of osteoporotic hip fracture in men; the multivariable-adjusted ORs (95% CIs) were 10.35 (1.90–56.39), and 2.71 (0.70–10.55), respectively. No substantial differences were observed in CXCL9 or CXCL10 levels in women [8].…”

“…Moreover, cellular senescence and vascular dysfunction can be reversed by inhibiting CXCL9 [6]. Elevated CXCL9 levels were associated with falls that occurred within the previous 1 year [7] and the risk of osteoporotic hip fractures in men during a follow-up of 6 years [8]. Similar findings were observed for CXCL10, although the statistical evidence was weak [7].…”

“…Considering that no previous study has investigated the association of CXCL9 and CXCL10 levels with frailty, we referred to a previous case-control study [8], which reported the association of CXCL9 and CXCL10 levels with the risk of hip fracture, to confirm the sample size. In that study, a sample size of 50 cases and 50 controls was considered to have more than 80% statistical power to detect estimates with a significance level of 0.05.…”

Unraveling the Bone Tissue Microenvironment in Chronic Lymphocytic Leukemia

“…The CXCL12/CXCR4 interaction, which is relevant in inducing CLL cell survival, proliferation and chemotaxis, also has remarkable influences on bone remodeling: through CXCR4, CXCL12 binding promotes osteoclastogenesis and induces osteogenic differentiation of mesenchymal stromal cells in cooperation with bone morphogenetic protein (BMP) signaling [37,41,42]. CXCL9, which is found at high concentrations in the sera of CLL patients and supposedly produced by stromal and activated B cells, also interferes with bone formation, further possibly favoring osteoclast differentiation and resorption [19,[43][44][45][46][47]. Given the evidence of the interferences of these chemokines in bone homeostasis [17] and their simultaneous release by CLL or stromal cells, it is feasible to foresee their possible participation in patient bone remodeling.…”