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Medications associated with fracture risk in patients with rheumatoid arthritis
  1. Gulsen Ozen1,
  2. Sofia Pedro2,
  3. Frederick Wolfe2,
  4. Kaleb Michaud1,2
  1. 1 University of Nebraska Medical Center, Omaha, Nebraska, USA
  2. 2 Forward, The National Databank for Rheumatic Diseases, Wichita, Kansas, USA
  1. Correspondence to Dr Kaleb Michaud, National Data Bank for Rheumatic Diseases, Wichita, KS 67214, USA; kmichaud{at}


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.

  • rheumatoid arthritis
  • fracture
  • opioids
  • antidepressants
  • statins
  • cohort study

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  • Handling editor Josef S Smolen

  • Contributors GO, SP and KM had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: all authors. Analysis of data: GO and SP. Interpretation of data and drafting of the manuscript: all authors.

  • Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement statement This research was done without patient involvement. Patients were not invited to comment on the study design and were not consulted to develop patient relevant outcomes or interpret the results. Patients were not invited to contribute to the writing or editing of this document for readability or accuracy.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by Via Christi Hospitals Wichita, Inc. Institutional Review Board (IRB#: IRB00001674 FWA#: FWA00001005).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No data are available.

  • Author note The lead author (the manuscript’s guarantor) affirms that the manuscript is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.