Sheffield, UK—NSAIDs used to reduce pain might have an unexpected and undesirable side effect: blocking the beneficial effects of bisphosphonates in protecting bone.

An international study published in the Journal of Bone and Mineral Research determined that the use of NSAIDs in more than 5,000 community-dwelling women aged 75 years and older did not appear to have a direct impact on individuals' bone fracture risk. Yet, the painkillers seemed to negate the bone-protective effects of the oral bisphosphonate, clodronate, in preventing osteoporotic fractures.

"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," explained senior author Eugene McCloskey, MD, of Northern General Hospital in the UK.

"Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to have weak but beneficial effects on bone health, including fracture risk, but many epidemiological studies are likely confounded," the authors wrote.

The study team sought to better understand the relationship between NSAIDs and fracture risk in a post hoc analysis of a well-documented, randomized, placebo-controlled study of the bisphosphonate, clodronate. In that study, treatment reduced osteoporotic fracture risk by 23%.

The authors noted that concurrent medication use at baseline was used to identify those prescribed oral NSAIDs. They said they included only verified incident fractures in the analysis.

With 20.8% of the women reporting use of NSAIDs at baseline, researchers pointed out that they were slightly, but significantly, younger (mean 79 vs. 80 years, P = .004), heavier (mean 66.7 vs. 64.7 kg, P <.001) than nonusers, with slightly higher femoral neck bone mineral density (BMD; 0.66 vs. 0.64 g/cm2, P <.001).

In an adjusted model, the study team found that NSAID use was associated with a significant increase in osteoporotic fracture risk over the 3-year study period (hazard ratio [HR] 1.27; 95% CI, 1.01-1.62; P = .039), although the increase in risk was not statistically significant in the placebo group (HR 1.11; 95% CI, 0.81-1.52).

"In women receiving clodronate, the effect of the bisphosphonate to reduce osteoporotic fracture risk was not observed in those receiving NSAIDs (HR 0.95; 95% CI, 0.65-1.41; P = .81) in contrast to those not using NSAIDs (HR 0.71; 95% CI, 0.58-0.89; P = .002)," the authors explained. "In a subset with hip BMD repeated at 3 years, BMD loss during clodronate therapy was greater in those women receiving NSAIDs than in nonusers (e.g., total hip -2.75% versus -1.27%, P = .078; femoral neck -3.06% versus -1.12%, P = .028), and was not significantly different from that observed in women receiving placebo."

The result, they noted, was that "the efficacy of the bisphosphonate, clodronate, to reduce fracture risk was largely negated in those receiving NSAIDs. Although the mechanism is unclear, this clinically significant observation requires exploration in studies of commonly used bisphosphonates."

Background information in the article recounts how NSAIDs are one of the most commonly prescribed medications for various acute and chronic musculoskeletal or inflammatory diseases. In the U.S., a recent survey indicated that 63% of adults reported having used NSAIDs within the past 12 months, and among patients aged 65 years and older, the prevalence of ever NSAID use could reach as high as 96.4%.

"NSAIDs commonly exert their anti-inflammatory and analgesic properties by inhibiting the synthesis of prostaglandins via cyclooxygenase enzymes (COX)," researchers advised. "Because prostaglandins, particularly prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2), are involved in bone remodeling, the relationship between NSAIDs use and fracture risks has been widely reported in the literature. However, conclusions derived from these studies are conflicting and variously suggest that NSAIDs use is a protective factor, a risk factor for fracture, or has no effect on fracture risk. Thus, the true impact of NSAIDs use on fracture risks, if any, remains unclear, reflecting the inability to adjust for other fracture-related risk factors in most of these studies."

At the same time, the authors indicated that bisphosphonates remain the most widely used therapeutic class in the treatment of various metabolic bone diseases associated with excessive bone resorption, especially osteoporosis.

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