Genetic Causal Link Found Between RA, Increased Fracture Risk

A genetic causal link exists between rheumatoid arthritis (RA) and an increased risk of traumatic and osteoporotic fractures, according to a recent Mendelian randomization (MR) study published in Medicine.¹

Past observational epidemiological studies demonstrated that the occurrence of various fractures was higher among those with RA vs the overall population. However, the associations reported in these studies cannot be considered reliable indicators of causal effects because of various confounding factors, like age, sex, and the interference of reverse causality.² Consequently, it remains unclear whether a causal relationship exists between RA and the risk of fractures, particularly traumatic and osteoporotic fractures.¹

Therefore, the researchers used the MR method to examine the potential causal relationship between RA and the risk of fractures. MR uses genetic variants as instrumental variables (IVs) to investigate the causal effects of a risk factor on an outcome; this makes it less prone to confounding issues and capable of establishing causal inferences.

A genetic causal link between rheumatoid arthritis (RA) and an increased risk of traumatic and osteoporotic fractures underscores the need for targeted prevention strategies. | Image Credit: VadimGuzhva - stock.adobe.com

More specifically, they performed an MR analysis using summary statistics from genome-wide association studies (GWAS) to explore the causal relationship between RA and the risk of traumatic fractures at 9 sites, as well as 3 types of osteoporotic fractures. The dataset was sourced from a comprehensive meta-analysis, which incorporated genetic data from multiple GWAS³; it comprised 14,361 cases and 43,923 controls.

Also, the researchers obtained the single nucleotide polymorphism (SNP) datasets for traumatic fractures at 9 different body sites, 3 types of osteoporotic fractures, and osteoporosis (OP) from the FinnGen biobank website.⁴

It comprised fractures at the following sites: shoulder and upper arm (11,750 cases; 345,173 controls); forearm (19,577 cases, 351,196); wrist and hand (11,394 cases; 336,418 controls); femur (8766 cases; 360,928 controls); lower leg, including the ankle (19,994 cases; 323,307 controls); foot, excluding the ankle (7593 cases; 351,392 controls); neck (1503 cases; 370,193 controls); rib(s) sternum, and thoracic spine (9094 cases; 362,260 controls); and lumbar spine and pelvis (6209 cases; 364,504 controls).

The dataset also included OP (7300 cases; 358,014 controls); OP with pathological fractures (1659 cases, 285,035 controls); postmenopausal OP (PMOP) with pathological fractures (1352 cases, 209,313 controls); and drug-induced OP with pathological fractures (357 cases, 375,618 controls).

The researchers used multiple techniques to evaluate the causal relationship between RA and fracture risk.¹ They primarily used the inverse-variance weighting (IVW) random effects model, which does not account for an intercept term in regression and assigns inverse outcome variance as weights, enabling unbiased causal inference. The researchers supplemented this model with MR-Egger regression and additional methods to assess causal relationships; they also performed sensitivity analyses, such as heterogeneity and pleiotropy assessments.

The IVW analysis demonstrated a causal relationship between genetically predicted RA and an increased risk for fractures at the following sites: shoulder and upper arm (OR, 1.041; 95% CI, 1.020-1.062); forearm (OR, 1.026; 95% CI, 1.007-1.044); femur (OR, 1.036; 95% CI, 1.009-1.064); lower leg, including ankle (OR, 1.031; 95% CI, 1.016-1.047); and rib(s), sternum, and thoracic spine (OR, 1.041; 95% CI, 1.018-1.064).

Similarly, the IVW analysis demonstrated a causal relationship between genetically predicted RA and OP (OR, 1.095; 95% CI, 1.063-1.128); OP with pathological fractures (OR, 1.128; 95% CI, 1.071-1.188), PMOP with pathological fractures (OR, 1.060; 95% CI, 1.002-1.123), and drug-induced OP with pathological fractures (OR, 1.255; 95% CI, 1.124-1.400).

Conversely, the researchers acknowledged their study’s limitations, including that it was based on data from European populations. They emphasized the need for further validation to explore race-specific differences in fracture risk due to RA. However, they remained confident in their findings.

“This study offers valuable perspectives for formulating treatment plans and preventive strategies for complications in patients with RA as well as new directions for future exploration of the mechanisms underlying RA-related fractures,” the authors concluded.

References

1. Zhang Y, Weng Q, Deng Z, Zhang H, Dai J, Chen X. Rheumatoid arthritis and the risk of fracture: A Mendelian randomization study. Medicine (Baltimore). 2025;104(3):e41248. doi:10.1097/MD.0000000000041248
2. Skrivankova VW, Richmond RC, Woolf BAR, et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ. 2021;375:n2233. doi:10.1136/bmj.n2233
3. Ha E, Bae SC, Kim K. Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis, identifying 11 novel susceptibility loci. Ann Rheum Dis. 2021;80(5):558-565. doi:10.1136/annrheumdis-2020-219065
4. Kurki MI, Karjalainen J, Palta P, et al. FinnGen provides genetic insights from a well-phenotyped isolated population. Nature. 2023;613(7944):508-518. doi:10.1038/s41586-022-05473-8