Context The receptor activator of nuclear factor κB ligand (RANKL) is
essential for osteoclast and, possibly, osteoblast activation and may represent
a key link between bone formation and resorption.
Objective To determine the relationship between serum level of RANKL and the risk
of nontraumatic fracture.
Design, Setting, and Participants As part of a prospective population-based study conducted in Bruneck,
Italy, we recorded all fractures that occurred between 1990 and 2000 in 906
participants and classified them as traumatic (n = 115) or nontraumatic (n
= 31). Serum levels of RANKL and osteoprotegerin and characteristics of bone
metabolism and lifestyle were assessed in 1990 and at follow-up in 1995 and
Main Outcome Measure Incident nontraumatic fracture by levels of RANKL.
Results Levels of RANKL did not differ between sexes and were not related to
age, menopausal status, lifestyle characteristics, or data from bone ultrasound
at the heel. However, RANKL emerged as a significant predictor of nontraumatic
fracture. In pooled logistic regression analysis, the relative risks of nontraumatic
fracture in the lowest and middle vs highest tertile for RANKL were 10.0 (95%
confidence interval [CI], 2.3-43.1) and 3.9 (95% CI, 0.8-19.0) (P<.001 for trend), respectively. Patients in the highest-tertile
group had a low risk of fracture even in the presence of other predisposing
factors, whereas women aged 60 years or older in the lowest tertile had a
5-year rate of nontraumatic fracture greater than 7%.
Conclusions A low level of RANKL is an independent predictor of nontraumatic fracture.
This finding is consistent with the hypothesis of an important role of RANKL
in human bone turnover and if confirmed in future investigations may gain
relevance for assessment of fracture risk.