Could NSAIDs Negate Bisphosphonate Benefits?

Nonsteroidal anti-inflammatory drugs (NSAIDs) seemed to neutralize the protective benefit of a certain bisphosphonate, according to a post-hoc analysis of a randomized controlled trial.

Among over 5,200 community-dwelling women ages 75 and older, those who were randomized to receive clodronate didn’t appear to have any reduced osteoporotic fracture risk if they were also using NSAIDs (HR 0.95, 95% CI 0.65-1.41, P=0.81), reported Eugene McCloskey, MD, of the University of Sheffield in England, and colleagues.

However, women taking clodronate who were not using NSAIDs reaped the protective benefits of the bisphosphonate, with a significant 29% reduction in osteoporotic fracture risk (HR 0.71, 95% CI 0.58-0.89, P=0.002), the group noted in the Journal of Bone and Mineral Research.

On top of that, in a model adjusted for age, femoral neck bone mineral density, weight, osteoarthritis, use of certain medications (such as for asthma/COPD and psycholeptics), sit-to-stand difficulty, and treatment group (clodronate vs placebo), NSAID use was tied to a 27% higher risk for all osteoporotic fractures among the entire trial population (HR 1.27, 95% CI 1.01-1.59), though this link didn’t extend to hip fractures (HR 0.98, 95% CI 0.60-1.61).

However, when the placebo group (those not on a bisphosphonate) was isolated, this increase in risk was not statistically significant (HR 1.11, 95% CI 0.81-1.52).

When looking at a subset of women who had bone mineral density screenings repeated after 3 years, those treated with clodronate who were also using NSAIDs saw greater bone mineral density loss than NSAID non-users at both the hip (-2.75% vs -1.27%, P=0.078) and femoral neck (-3.06% vs -1.12%, P=0.028).

“We need to exercise some caution in extrapolating these data to more widely used bisphosphonates in osteoporosis, but given that concomitant usage of NSAIDs and bisphosphonates is relatively common, this could have major clinical consequences and result in a failure to reduce fracture risk as much as we had hoped,” McCloskey said in a statement.

“The marked reduction in efficacy does not appear to be mediated by imbalances in baseline characteristics or lower compliance,” the researchers pointed out.

While many types of bisphosphonates are widely used to prevent osteoporotic fractures, clodronate in particular is not currently FDA-approved in the U.S.

This analysis included 5,212 women taking either 800 mg daily of clodronate or identical placebo. Participants did not receive calcium or vitamin D supplementation. Bone mineral density was measured via dual-energy X-ray absorptiometry (DXA) at the total hip and subregions. During the 3-year follow-up period, 440 women experienced at least one new osteoporotic fracture.

Of the total cohort, 21% self-reported that they used NSAIDs at baseline, the most common being ibuprofen and diclofenac. Users of NSAIDs tended to be younger, have a higher BMI, and more frequently reported histories of osteoarthritis and rheumatoid arthritis.

“Although possible mechanisms need further exploration, there is an urgent need to examine this interaction in studies of other bisphosphonates in osteoporosis and other bone diseases,” McCloskey’s group advised.