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Medications used by patients with rheumatoid arthritis (RA) can significantly influence these patients' already increased risk of fractures -- for better or for worse, a large longitudinal study found.

For instance, elevated fracture risk was observed with either the use of weak opioids (HR 1.37, 95% CI 1.18-1.59) or strong opioids (HR 1.53, 95% CI 1.24-1.88) and with selective serotonin reuptake inhibitors, or SSRIs (HR 1.37, 95% CI 1.15-1.63), according to Kaleb Michaud, MD, of the National Data Bank for Rheumatic Diseases in Wichita, Kansas, and colleagues.

In contrast, decreased risks for vertebral fractures were seen with the use of statins (HR 0.77, 95% CI 0.62-0.96) and tumor necrosis factor (TNF) inhibitors (HR 0.72, 95% CI 0.54-0.97), the researchers reported online in .

Patients with RA have double the risk of osteoporosis and fractures compared with the wider population. Moreover, "chronic inflammation, physical inactivity, and glucocorticoids mediating the increased osteoporosis and fracture risk also predispose patients with RA to multiple comorbidities including cardiometabolic, mood, sleep, and gastrointestinal disorders, which in turn correlate with disability and mortality," Michaud and colleagues wrote.

In the general population, numerous medications have been reported to increase the risk of fractures, including proton pump inhibitors, SSRIs, benzodiazepines, nonsteroidal anti-inflammatory drugs, and opioids. In RA, however, data on fracture risks with drugs have been sparse with the exception of opioids, which have been shown in previous studies to raise the risks of nonvertebral fractures.

But earlier studies have not considered important factors such as disease activity, BMI, physical activity, and smoking that could further affect fracture risks, so Michaud's group analyzed data from RA patients enrolled in FORWARD -- The National Databank for Rheumatic Diseases, from 2003 to 2017.

Detailed information was obtained about clinical risk factors, medication exposures, and sociodemographic factors for 11,412 patients with RA whose mean age at baseline was 61.4 and with an average 15.6 year disease duration.

During a median of 3 years of follow-up (55,482 patient-years), there were 914 first-time fractures, for a crude incidence rate of 16.5 per 1,000 patient-years.

Patients who developed fractures typically were older women with long disease duration, higher disease activity, more comorbidities, and greater use of glucocorticoids, opioids, and antidepressants than those without fractures.

In fully adjusted models, fracture risks were increased with use of glucocorticoids for 3 months or longer, both at daily doses below 7.5 mg (HR 1.26, 95% CI 1.07-1.48) and 7.5 mg/day or higher (HR 1.57, 95% CI 1.27-1.94).

In comparison with methotrexate monotherapy, other synthetic DMARDs were associated with lower fracture risk (HR 0.82, 95% CI 0.69-0.99).

The researchers also looked at risks associated with ever use and duration for opioids and SSRIs. For both classes of drugs, there was an increased risk for ever use (vs never use) for opioids (HR 1.45, 95% CI 1.25-1.68) and for opioids and SSRIs (HR 1.18, 95% CI 1-1.39).

With opioids, the risks were most prominent during the first 30 days of treatment (HR 1.66, 95% CI 1.36-2.04), which declined for months 1 to 3 (HR 1.46, 95% CI 1.20-1.78) and after 3 months (HR 1.35, 95% CI 1.12-1.64). For SSRIs, the fracture risk only began to increase after 3 months (HR 1.25, 95% CI 1.01-1.55).

In a subgroup of 6,899 patients who were never diagnosed or treated for osteoporosis, there were 240 incident fractures. Once again, fracture risks were increased for opioids (HR 1.26, 95% CI 1.01-1.72) and SSRIs (HR 1.86, 95% CI 1.32-2.62).

When vertebral and nonvertebral fractures were analyzed separately, the incidence rates were 7.7 per 1,000 and 10.1 per 1,000 patient-years, respectively. For vertebral fractures, risks were increased for both opioids (HR 1.83, 95% CI 1.48-2.26) and SSRIs (HR 1.50, 95% CI 1.18-1.91), while for nonvertebral fractures, only opioids showed an increased risk (HR 1.29, 95% CI 1.07-1.56).

Potential mechanisms by which opioids could increase fractures include raising the risk of falls and effects on bone metabolism, but that greatest risk during the first month of exposure suggests that fall risk is the more likely mechanism, the researchers noted. In contrast, the elevated fracture risk associated with SSRIs increased with longer use, so bone metabolism effects may be involved.

The potential benefits of statins may relate to anabolic and anti-osteoclastic effects, and the protective influence of TNF inhibitors may arise from these agents' powerful anti-inflammatory effects.

Osteoporotic fractures are an important cause of both morbidity and mortality in RA, so recognition of potentially modifiable risk factors such as medications, is crucial.

"We suggest a regular review of the necessity of the medications being used," Michaud and colleagues advised. "In the opioid epidemic era, to avoid fractures and other devastating consequences, opioid use should be minimized for pain management in RA," they concluded.

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