Objective To examine the fracture risk with use of disease-modifying antirheumatic drugs (DMARDs), statins, proton pump inhibitors (PPIs), opioids, non-opioid analgesics and psychotropic medications in a US-wide observational rheumatoid arthritis (RA) cohort.

Methods Patients with RA without prior fracture from 2001 through 2017 in FORWARD, a longitudinal observational registry, were assessed for osteoporosis-related site fractures (vertebra, hip, forearm and humerus). DMARD exposure was assessed in four mutually exclusive groups: (1) methotrexate monotherapy-reference, (2) tumour necrosis factor-α inhibitors (TNFi), (3) non-TNFi biologics and (4) others. Non-DMARDs and glucocorticoids were classified as current/ever use and based on treatment duration. Fracture Risk Assessment Tool (FRAX) scores estimating for 10-year major osteoporotic fractures were calculated. Cox proportional hazard models stratified by FRAX were used to adjust for confounders.

Results During median (IQR) 3.0 (1.5–6.0) years of follow-up in 11 412 patients, 914 fractures were observed. The adjusted models showed a significant fracture risk increase with use of any dose glucocorticoids ≥3 months (HR (95% CI) for <7.5 mg/day 1.26 (1.07 to 1.48) and for ≥7.5 mg/day 1.57 (1.27 to 1.94)), opioids (for weak: 1.37 (1.18 to 1.59); strong: 1.53 (1.24 to 1.88)) and selective serotonin reuptake inhibitors (SSRIs) (1.37 (1.15 to 1.63)). Fracture risk with opioids increased within 1 month of use (1.66 (1.36 to 2.04)) and with SSRIs >3 months of use (1.25 (1.01 to 1.55)). Statins (0.77 (0.62 to 0.96)) and TNFi (0.72 (0.54 to 0.97)) were associated with reduction in vertebral fracture risk only. PPIs and other psychotropic medications were not associated with increased fracture risk.

Conclusion Use of opioids, SSRIs and glucocorticoids were associated with increased risk of any fracture in patients with RA, whereas statins and TNFi were associated with decreased vertebral fractures.