There were no differences in risk of nonvertebral fragility fractures among patients with rheumatoid arthritis (RA) according to their use of individual biologic and targeted synthetic disease-modifying antirheumatic drugs (DMARDs), a large cohort study found.
Compared with new users of adalimumab (Humira; chosen as the reference agent because of frequency of use), the adjusted propensity score-weighted hazard ratios for fracture ranged from 0.91 (95% CI 0.59-1.39) for golimumab (Simponi) to 1.24 (95% CI 0.71-2.17) for tocilizumab (Actemra), with none being statistically significant differences, reported Seoyoung C. Kim, MD, ScD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, and colleagues.
“These findings may be reassuring to physicians prescribing biologic/targeted synthetic DMARDs to patients with RA,” the researchers wrote online in ACR Open Rheumatology.
Patients with RA have almost twice the risk for osteoporosis compared with the general population, and have a 2.25 times higher risk for fracture. However, the evidence concerning the influence of medications on fracture risk has been sparse and conflicting, and few data exist for risks among the widely used individual biologic or targeted synthetic DMARDs.
Kim’s group analyzed data from the Medicare, Optum, and MarketScan databases, which include more than 200 million patients, for the years 2008 to 2019.
Along with adalimumab and tocilizumab, the agents included in the analysis were abatacept (Orencia), certolizumab (Cimzia), etanercept (Enbrel), golimumab, infliximab (Remicade), rituximab (Rituxan), and tofacitinib (Xeljanz).
The primary outcome was the occurrence of a nonvertebral fragility fracture of the hip, humerus, pelvis, or wrist. Covariates included demographics, time of year, comorbidities and frailty, medication exposure, and healthcare usage.
The new-user cohort included 134,693 patients. For the individual drugs, the number of new users ranged from 35,305 for adalimumab to 3,499 for tocilizumab.
Mean age was 72 among Medicare patients, and 54 and 52 in the Optum and MarketScan groups, respectively. During the year prior to starting a biologic or targeted synthetic DMARD, 39-65% of patients had been treated with methotrexate and 64% to 71% with corticosteroids.
During 158,027 person-years of follow-up, there were 1,234 nonvertebral fractures overall, for an incidence rate of 7.81 (95% CI 7.38-8.26) per 1,000 person-years, the researchers reported.
For the individual fracture sites, the incidence rates per 1,000 person-years were:
- 3.14 (95% CI 2.87-3.43) for the hip
- 2.72 (95% CI 2.47-2.99) for the wrist
- 1.73 (95% CI 1.53-1.95) for the humerus
- 0.50 (95% CI 0.39-0.62) for the pelvis
The incidence rate for the composite endpoint among patients starting adalimumab was 5.10 (95% CI 4.40-5.88) per 1,000 person-years, while the incidence rates among initiators of the other agents ranged from 5.67 (95% CI 4.95-6.46) per 1,000 for etanercept to 11.88 (95% CI 8.56-16.05) per 1,000 for tofacitinib.
After propensity score weighting, none of the hazard ratios compared with adalimumab for the remaining medications were statistically significant:
- Abatacept, HR 1.03 (95% CI 0.82-1.30)
- Certolizumab, HR 1.08 (95% CI 0.79-1.49)
- Etanercept, HR 1.12 (95% CI 0.89-1.40)
- Infliximab, HR 1.03 (95% CI 0.84-1.28)
- Rituximab, HR 1.07 (95% CI 0.74-1.55)
- Tofacitinib, HR 1.07 (95% CI 0.69-1.64)
In a secondary analysis, similar results were seen for the individual fracture sites, with no significant risk elevations for any of the agents, with the exception of a lower risk of wrist fracture with golimumab, which may reflect random chance or small numbers, the investigators said.
In addition, while there were more events in the older Medicare group, again the hazard ratios after propensity score weighting were similar across age groups.
In an additional secondary analysis of patients who switched to another medication after using a tumor necrosis factor inhibitor, the incidence rate for the composite outcome was higher than for new users, at 8.22 (95% CI 7.43-9.08) per 1,000 person-years, but this likely resulted from patients having more advanced disease, Kim and co-authors noted.
“Our results are clinically meaningful because they will help rheumatologists who are concerned about the risk of fractures make an appropriate treatment choice in patients with RA, particularly for those at a higher risk of nonvertebral fractures,” the team wrote.
Strengths of the study, the researchers said, included its large size and real-world setting, while limitations included the possibility of residual confounding and a lack of information in the databases on factors such as diet, body mass index, and RA severity.
Last Updated July 07, 2021
The study was supported by Bristol Myers Squibb.
Kim reported research grants to Brigham and Women’s Hospital from Roche, Pfizer, AbbVie, and Bristol Myers Squibb for other studies; a co-author reported serving as the principal investigator on research grants from Vertex, Bayer, and Novartis to Brigham and Women’s for unrelated projects.
The researchers reported financial relationships with Bristol Myers Squibb, Vertex, Bayer, Novartis, Roche, Pfizer, and AbbVie.