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NEW YORK (Reuters Health) – Nonsteroidal anti-inflammatory drugs (NSAIDs) showed signs of counteracting the effects of bisphosphonate on bone, according to new research.

An exploratory post hoc analysis of data from a randomized clinical trial (RCT) found women taking clodronate plus an NSAID saw a 49% adjusted increase in their risk of osteoporotic fractures compared with women on clodronate who weren’t using NSAIDs, researchers report in the Journal of Bone and Mineral Research.

“The RCT with which we undertook this analysis allowed us to adjust for many of the other variables that impact on bone health and might differ between NSAID users and non-users,” Dr. Eugene McCloskey of the University of Sheffield, in the U.K. told Reuters Health by email.

“The lack of any effect in the placebo group of the study was reassuring,” he added. “But the impact (of NSAID) to reduce the effect of bisphosphonate was quite a surprise.”

The original clinical trial involved 5, corticosteroids prednisone 212 women 75 years or older from Sheffield and the surrounding area. Exclusion criteria included evidence of metabolic bone disease, calcium disorders and other potential confounding factors.

At baseline, 21% of women reported use of NSAIDs, most commonly ibuprofen and diclofenac. These women were slightly younger (mean, 79 vs. 80 years, P=0.004), heavier (mean, 67 vs. 65 kg, P<0.001) and had a higher femoral-neck bone-mineral density (FN-BMD, 0.66 vs. 0.64 g/cm2, P<0.001) than women not using NSAIDs.

Despite these differences, the authors say these and other characteristics were “well-balanced between those randomized to receive clodronate or placebo in the presence or absence of NSAID.”

Following randomization, the women received either 800 mg of clodronate daily, as two 400-mg BONEFOS tablets once daily or one tablet twice daily, or an identical placebo.

At least one incident of osteoporotic fracture occurred in 440 women during the follow-up period, which was the same for both NSAID users and nonusers (mean, 2.77 years). Hip fractures accounted for 110 of these fractures.

Among the placebo group, the rates of osteoporotic and hip fractures did not differ between the groups with (9.5%) or without (9.7%) NSAID use. Among the women treated with clodronate, however, NSAID use was linked to a 49% higher risk of osteoporotic fracture (P=0.019) after adjustment for confounders.

For the entire study population, the hazard ratio for osteoporotic fracture was 1.27 with versus without NSAID use (P=0.039).

Among the women who received clodronate, bisphosphonate’s documented ability to reduce the risk of osteoporotic fracture was not observed in the group also taking NSAIDs (HR, 0.95; P=0.81), while it was clear in women not taking NSAIDs (HR, 0.71; P=0.002).

In a subset for whom BMD measurements were repeated at three years, loss in BMD while using clodronate was found to be greater in women treated with NSAIDs than without (total hip, 2.75% vs. 1.27%, P=0.078; femoral neck, 3.06% vs. 1.12%, P=0.028). By comparison, no significant difference was recorded in women receiving a placebo instead of clodronate.

The potential underlying mechanism is still unclear, the researchers note.

“The low bioavailability (of clodronate) is an obvious mechanism that might explain these findings but again this can’t be answered within our study or analysis,” Dr. McCloskey noted. “These data are too limited as yet to give any advice to clodronate or other bisphosphonate users about dosing.”

Dr. Nazir Noor, chief resident physician at Mount Sinai Medical Center Miami Beach, described the study as “definitely interesting and something to consider, but not before larger trials with a variety of bisphosphonates are completed.”

Dr. Noor, who was not involved in the study, has collaborated on a comprehensive review of NSAIDs, bisphosphonates, and other medications in the management of complex regional pain syndrome (CRPS). He said the new addresses “something that may be often overlooked.”

“It brings up an important discussion for clinicians when considering a commonly administered class of medications, such as NSAIDs,” Dr. Noor told Reuters Health by email.

SOURCE: https://bit.ly/3kLSGb9 Journal of Bone and Mineral Research, online April 20, 2022.

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