Lower BMD tied to endothelial dysfunction in RA

Patients with rheumatoid arthritis (RA) who have lower bone mineral density (BMD) are more likely to experience endothelial dysfunction but not aortic stiffness, suggests a Singapore study. 

“To validate the findings, future research should focus on longitudinal studies, mechanistic studies, and broader vascular health assessments,” the researchers said. 

This cross-sectional study involved 49 RA patients at the Tan Tock Seng Hospital, Singapore. Researchers measured endothelial function as reactive hyperaemia index (RHI)-endothelial peripheral arterial tonometry and aortic stiffness as carotid–femoral pulse wave velocity (cf-PWV) using SphygmoCor. 

The associations between BMD and vascular function were assessed via univariable and multivariable linear regression analyses. Natural logarithm RHI (lnRHI) and cf-PWV were used as response variables and each BMD as covariate, with adjustments for BMI, positive anticyclic citrullinated peptide, cumulative prednisolone dose, hydroxychloroquine use, and Systematic Coronary Risk Evaluation 2. 

Of the 49 patients (mean age 61.08 years) recruited, 44 (89.80 percent) were women and 39 (81.25 percent) were Chinese. [Singapore Med J 2025;66:147-153] 

Univariable analyses revealed significant associations between lnRHI and BMD at the lumbar spine (β=0.4289; p=0.037) and total hip (β=0.7544; p=0.014). These associations persisted in multivariable analyses, which revealed the significant correlation of lower BMD at the lumbar spine (β=0.7303; p=0.001), femoral neck (β=0.8694; p=0.030), and total hip (β=0.8909; p=0.010) with worse lnRHI. 

On the other hand, BMD showed no significant association with cf-PWV. 

“Our findings on the associations between BMD and endothelial dysfunction in RA align with previous studies conducted in postmenopausal women, the very elderly, and those with early coronary atherosclerosis,” the researchers said. [Atherosclerosis 2004;176;387-392; Circ J 2007;71;1555-1559; Atherosclerosis 2020;292;70-74; Vasc Health Risk Manag 2014;10;533-538] 

Another study found an association between endothelial dysfunction and osteoprotegerin, an inhibitor of osteoclastogenesis, but not BMD in RA. [Clin Exp Rheumatol 2015;33;241-249] 

“However, our study demonstrated a consistent association between BMD and endothelial dysfunction in RA,” the researchers said. 

Mechanisms 

The association between BMD and endothelial dysfunction can be explained by several mechanisms. For instance, nitric oxide that is synthesized by endothelial nitric oxide synthase (eNOS) maintains vascular homeostasis and endothelial function and impacts bone remodeling by promoting osteoblast activity and inhibiting osteoclast activity. [J Clin Invest 2021;131;e147072] 

CTAAAT, a genetic variant of eNOS, is also predictive of the association between endothelial dysfunction and osteoporosis in postmenopausal women. [Int J Environ Res Public Health 2021;18;972] 

Second, there is the involvement of the receptor activation of nuclear factor kappa-B (RANK)/RANKL/OPG system, which is crucial in both vascular health and bone metabolism. [Int J Mol Sci 2019;20;705] 

In addition, the association between BMD and endothelial dysfunction in postmenopausal women “suggests a potential synergistic effect of oestrogen deficiency.” [J Indian Coll Cardiol 2018;8;14-17] 

Oestrogen deficiency contributes to the exacerbation of oxidative stress and inflammation, increased reactive oxygen species, and dysregulation of the RANK/RANKL/OPG system. [J Clin Invest 2006;116;1186-1194] 

“Furthermore, shared risks for endothelial dysfunction and bone health impairment are known in RA, that is, the use of glucocorticoids, hydroxychloroquine, and systemic inflammation,” the researchers said. “Therefore, the finding of an association between endothelial dysfunction and decreased BMD is plausible in RA.” [Arthritis Res Ther 2019;21;15]