The Relationship between Cytokines, Bone Turnover Markers, and Bone Mineral Density Following Hip Fracture

Abstract

The RANK/RANKL/OPG system and inflammation are critical to bone remodeling. However, little is known about the relationships among OPG, RANKL, inflammatory cytokines, bone turnover markers (BTM) and bone mineral density (BMD) in persons with hip fracture (HipFx). The objective of the present analysis was to examine the relationships between serum biomarkers of OPG, RANKL, IL-6, TNF-α and BTM and BMD after HipFx and compare these relationships between men and women. Baltimore Hip Studies cohort 7 (BHS7) is a longitudinal study of sex differences in functional, physiologic, and metabolic consequences of HipFx. Serum from BHS7 participants was analyzed for OPG, RANKL, IL-6, sTNF-αR1, PINP and CTX. BMD was measured by bone densitometry. Assessments were made at baseline (within 15 days of hospitalization) and 2 and 6 months after fracture. Generalized estimating equations (GEE) modeled the associations of OPG, RANKL, RANKL/OPG and inflammatory cytokines with BTM and BMD over time, adjusting for covariates. Analyses included 151 participants (75 men, 76 women), aged 65 years and older (mean [SD] = 81.5 [7.6] years). Higher levels of OPG were associated with higher femoral neck (p=0.0002) and total hip BMD (p=0.04). After stratification by sex, this relationship remained significant in both men and women with femoral neck BMD (p=0.04 and 0.003, respectively) and in men only with total hip BMD (p=0.005). Across all participants and in women only, sTNF-αR1 was positively associated with CTX (p=0.04 and 0.02, respectively). In men, sTNF-αR1 was positively associated with femoral neck and total hip BMD (p=0.004 and 0.01, respectively). Detectable RANKL values and IL-6 were not significantly associated with BTM or BMD either overall or in sex-specific analyses. The relationship between RANKL/OPG measure and BMD followed similar patterns as OPG, with the exception of sex differences in significance associations. Data demonstrate that serum OPG is positively associated with BMD and TNF-α with CTX, with lower OPG concentrations contributing to the excess decline in BMD and lower TNF-α to greater bone resorption after HipFx. Although non-significant, differences seen in the relationship between biomarkers and BTM and BMD suggest that men and women may experience variations in the fracture recovery process.