Combo Tx for RA Raises Fracture Risk

Patients with rheumatoid arthritis (RA) who were treated with oral glucocorticoids and proton pump inhibitors (PPIs) were at increased risk for osteoporotic fracture, a large cohort study found.

Patients who were concomitant users of glucocorticoids and PPIs had a 1.6-fold increased risk of osteoporotic fracture (adjusted HR 1.60, 95% CI 1.35-1.89), reported Frank de Vries, PharmD, PhD, of Utrecht University in the Netherlands, and colleagues.

In contrast, for those who used either oral glucocorticoids or PPIs alone, the risk was only 1.2-fold higher. For glucocorticoid use alone, the adjusted hazard ratio was 1.23 (95% CI 1.03-1.47), while for PPI use the hazard ratio was 1.22 (95% CI 1.05-1.42), which were statistically lower than for concomitant use of the two, according to the team’s study online in Annals of the Rheumatic Diseases.

Patients with RA are known to be at increased risk for osteoporotic fractures, both from the systemic inflammation underlying the disease and from the medications — particularly glucocorticoids — used for treatment.

RA patients are also frequently prescribed other medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) for analgesia, along with PPIs to lower the risk of NSAID-associated gastrointestinal adverse events.

Studies looking at the potential effects on fracture risk with PPIs have shown conflicting results, with some suggesting a causal association but others failing to demonstrate plausible relationships.

For example, a population-based study found a 2.4-fold elevated risk for hip fracture in patients taking high-dose glucocorticoids and PPIs, but no studies have specifically considered the effects of concomitant use among older patients with RA.

Accordingly, de Vries and co-authors analyzed data from the U.K. Clinical Practice Research Datalink, which is a primary care database that includes medical records from 674 practices and 4.4 million patients.

The study cohort included 12,351 adults age 50 and older diagnosed with RA from 1997 to 2017. Patients were stratified according to daily and cumulative doses and duration of treatment, and the primary outcome was a first osteoporotic fracture after RA diagnosis, including hip, symptomatic vertebral, humerus, forearm, pelvis, and rib fractures.

Two-thirds of the patients in the study were women. Mean age of patients who were concomitant users of glucocorticoids and PPIs was 67.5 vs 69 for non-users. Mean duration of follow-up was 9.1 years for concomitant users vs 5.1 years for those who used neither treatment.

In the 6 months before the diagnosis of RA, 54% of those who subsequently were concomitant users had been given nonselective NSAIDs, as were 48% of non-users. Mean duration of use was 3.3 years for glucocorticoids (whether concomitant or alone) and 4.1 years for PPIs alone.

No increased fracture risk was observed for patients who had stopped treatment with oral glucocorticoids or PPIs for more than 6 months.

Regarding the risks for specific fracture sites, the researchers found increased adjusted risks among concomitant users of glucocorticoids and PPIs for these sites:

• Hip, HR 1.45 (95% CI 1.11-1.91)

• Clinical vertebral, HR 2.84 (95% CI 1.87-4.32)

• Pelvis, HR 2.47 (95% CI 1.41-4.34)

• Rib, HR 4.03 (95% CI 2.13-7.63)

No increased risk was observed for the forearm or humerus. There was also no increase in fracture risk with higher daily doses of PPIs, and while fracture risk was increased with PPI use of less than 1 year, the risk was no longer present after a year of use, the investigators reported.

They explained that the effects of glucocorticoids on bone are primarily due to decreasing formation of bone and blocking bone remodeling sites, although muscle atrophy may also play a role.

However, the specific mechanisms by which PPIs might influence fracture risk are less clear, the team continued. In 2011, the FDA issued a drug safety communication about a possible increase in fracture risk with high-dose PPIs, but de Vries et al. later criticized that “for not being supported by a clear biological mechanism.”

Potential explanations for the negative effects on fracture risk with PPI use include a reduction in the intestinal absorption of calcium, reductions in vitamin B12 levels, and enhancement of osteoclast bone resorption, although more research is needed to determine the exact biological mechanism of PPIs on bone, the team wrote.

“Considering the increasing life expectancies and high consumption of PPIs among elderly patients, fracture risk assessment could be considered when a patient with RA is co-prescribed oral glucocorticoids and PPIs,” the researchers concluded.

A limitation of the study, they said, was that there was incomplete information in the database on disease activity and severity.