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Soluble RANKL and Risk of Nontraumatic Fracture
Georg Schett, MD;
Stefan Kiechl, MD;
Kurt Redlich, MD;
Friedrich Oberhollenzer, MD;
Siegfried Weger, MD;
Georg Egger, MD;
Agnes Mayr, MD;
Josef Jocher, MD;
Qingbo Xu, MD;
Peter Pietschmann, MD;
Steven Teitelbaum, MD;
Josef Smolen, MD;
Johann Willeit, MD
JAMA. 2004;291:1108-1113.
Context The receptor activator of nuclear factor  B 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 2000.
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.
Author Affiliations: Department of Internal Medicine III, Division of Rheumatology (Drs Schett, Redlich, and Smolen), and Department of Pathophysiology (Dr Pietschmann), University of Vienna, Vienna, Austria; Department of Neurology, University Clinic of Innsbruck, Innsbruck, Austria (Drs Kiechl and Willeit); Departments of Internal Medicine (Drs Oberhollenzer, Weger, and Egger), Laboratory Medicine (Dr Mayr), and Radiology (Dr Jocher), Bruneck Hospital, Bruneck, Italy; Department of Cardiological Sciences, St George's Hospital Medical School, London, England (Dr Xu); and Department of Pathology, Washington University School of Medicine, St Louis, Mo (Dr Teitelbaum).
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