RANKL, osteoprotegerin, and the risk of low trauma hip fracture in postmenopausal women

Identifying risk factors of osteoporotic hip fracture is important in our aging population given the physical and economic burdens incurred. The objective of this study was to assess prospectively the association of two bone turnover regulators, receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) with the risk of osteoporotic hip fracture, using the resources of the New York University Women's Health Study (NYUWHS). The endpoint of the study was low-trauma hip fracture, which was shown in a preliminary study to be accurately assessed by self-report. Prior to the start of the nested case-control study, the temporal reliability of OPG and RANKL was also examined, and it was shown that a single measurement in an individual reflects reasonably well the long-term average level within this individual (intraclass correlation coefficients (ICCs) for RANKL and OPG were 0.80 and 0.75, respectively). Out of 14,274 women in the NYUWHS cohort, 116 low-trauma hip fracture cases were identified among participants who were postmenopausal at baseline. Incidence density sampling was used to select two controls for each case (total = 232 controls), matching the case on age at, and date of, blood donation. Using in-house sandwich Enzyme-Linked Immunosorbent Assays (ELISAs), baseline RANKL and OPG in serum were measured and compared between cases and controls. For RANKL, whereas no association was observed overall, there was evidence of effect modification by age at blood donation. RANKL levels were higher in cases than in controls among women ≤60, but lower among women >60 years of age. The odds ratio (OR) for hip fracture was 1.31(95% CI: 1.01, 1.71) for women age 60 or below, and 0.85 (95% CI: 0.68, 1.08) for women over the age of 60. OPG increased with age in both cases and controls (P=0.10 and P=0.004, respectively), but the association between OPG levels and hip-fracture risk was not significant in any age group. Overall, the study suggests that RANKL is associated with the risk of osteoporotic hip fracture but that this association varies according to age, whereas OPG is not associated with risk. These findings require replication in larger studies.