Elevated Adipokines an Independent Risk Factor for Fracture in RA

Patients with rheumatoid arthritis (RA) have a higher risk of osteoporotic fractures if they have elevated adipokines, according to a recent report.¹ However, the investigators behind the study, which was published in the journal Arthritis Care & Research, say further research is needed to better understand the reasons behind the association.

Corresponding author Joshua F. Baker, MD, MSCE, of the Perelman School of Medicine at the University of Pennsylvania, and colleagues, noted that RA has already been linked with a higher risk of osteoporosis and osteoporotic fracture.² A 2011 study of women with arthritis found that women with RA had a hazard ratio (HR) of 1.49 for fractures, compared to women without arthritis. Baker and colleagues said a number of potential reasons for the association have been proposed.¹

“The cause of this increased risk of fracture is multifactorial and thought to be related to the effects of chronic inflammation of bone, reduced physical activity, excess glucocorticoid use, and altered body composition,” they explained.

The notion that altered body composition might impact fracture risk raises the possibility that adipokines might play a role, as adipokines are protein hormones secreted by fat and muscle that help regulate metabolism. Adipokines have already been linked with body composition abnormalities, such as excess and visceral adiposity, the authors noted. Previous research has suggested that one type of adipokine, adiponectin, is associated with a higher risk of fracture in older males; the association was not significant in older females.³

Furthermore, Baker and colleagues said adipokines have been found to be disrupted in patients with RA and have been linked with disease activity and poor outcomes.⁴

All of this led the investigators to wonder whether levels of circulating adipokines might be associated with fracture risk among patients with RA, specifically.¹ They used banked serum samples from 2527 people who participated in a longitudinal RA study. Patients’ adipokine levels were classified into either high or low classes. The investigators then used published algorithms and diagnostic codes to identify incident osteoporotic fractures and confirmed those fractures by chart review.

The cohort of patients was primarily men (89%), and the cohort had a median age of 72 years. Altogether, the study period included more than 27,540 person-years. With 228 total incident fractures reported, there were 8.3 fractures per 1,000 person-years, the authors found.

After adjusting for several factors, including age, sex, race, smoking status, body mass index, prednisone use, and disease activity, among others, the investigators found that elevated levels of all 3 adipokines studied—adiponectin, leptin, and fibroblast growth factor 21 (FGF-21)—were associated with an increased risk of fracture. Patients with high leptin levels had an HR for fracture of 1.47 (95% CI, 1.15-1.90; P = .003). Patients with elevated FGF-21 had a fracture HR of 1.39 (95% CI, 1.16-1.67; P < .001). Patients with elevated adiponectin had an HR for fracture of 1.21 (95% CI, 0.94-1.55), though that elevated risk did not achieve statistical significance (P = .13).

“This study demonstrated associations between circulating adipokines and the risk of incident OP (osteoporotic) fractures among patients with RA,” the authors said.

They noted, however, that the highest risk was found among patients who had elevated levels of all 3 adipokines (HR 2.17; 95% CI, 1.27-3.70; P = .005).

Though the findings support the idea that elevated levels of certain adipokines are independent predictors of fracture risk, the investigators said more study is needed to better understand exactly why adipokines are associated with fracture risk. Two possibilities, the authors noted, are that the connection stems from altered body composition or disrupted metabolic pathways.

References

1. Baker JF, England BR, George MD, et al. Adipokines and associations with incident osteoporotic fracture in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). Published online August 18, 2025. doi:10.1002/acr.25632
2. Wright NC, Lisse JR, Walitt BT, Eaton CB, Chen Z; Women's Health Initiative Investigators. Arthritis increases the risk for fractures—results from the Women's Health Initiative. J Rheumatol. 2011;38(8):1680-1688. doi:10.3899/jrheum.101196
3. Barbour KE, Zmuda JM, Boudreau R, et al. Adipokines and the risk of fracture in older adults. J Bone Miner Res. 2011;26(7):1568-1576. doi:10.1002/jbmr.361
4. Magali Chamorro-Melo Y, Calixto OJ, Bello-Gualtero JM, Bautista-Molano W, Beltran-Ostos A, Romero-Sánchez C. Evaluation of the adipokine profile (adiponectin, resistin, adipsin, vaspin, and leptin) in patients with early rheumatoid arthritis and its correlation with disease activity. Reumatologia. 2022;60(3):192-199. doi:10.5114/reum.2022.117839