Emerging evidence that adaptive bone formation inhibition by non-steroidal anti-inflammatory drugs increases stress fracture risk

Abstract

There is mounting evidence suggesting that the commonly used analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), may inhibit new bone formation with physical training and increase risk of stress fractures in physically active populations. Stress fractures are thought to occur when bones are subjected to repetitive mechanical loading, which can lead to a cycle of tissue microdamage, repair, and continued mechanical loading until fracture. Adaptive bone formation, particularly on the periosteal surface of long bones, is a concurrent adaptive response of bone to heightened mechanical loading that can improve the fatigue resistance of the skeletal structure, and therefore may play a critical role in offsetting the risk of stress fracture. Reports from animal studies suggest that NSAID administration may suppress this important adaptive response to mechanical loading. These observations have implications for populations such as endurance athletes and military recruits who are at risk of stress fracture and whose use of NSAIDs is widespread. However, results from human trials evaluating exercise and bone adaptation with NSAID consumption have been less conclusive. In this review, we identify knowledge gaps that must be addressed to further support NSAID-related guidelines intended for at-risk populations and individuals.

Regular Non-steroidal Anti-inflammatory Drug Use Increases Stress Fracture Risk in the General Population: A Retrospective Case-Control Study

“…Next, our laboratory investigated the impact of these NSAIDs in a preclinical mouse model 6 . Here, we observed a significant impact of the NSAID naproxen to decrease load-induced bone formation, as observed with NSAID administration in previous studies, as well as a novel deleterious effect on bone toughness 3,5,8,12,13 . We expect that both effects would increase stress fracture incidence, particularly when taken regularly.…”

“…In addition to being the most popular NSAID category in our cohort, the drugs within the ADVIL category are potent COX2 inhibitors. As a result, subjects taking the ADVIL NSAIDs are likely to have decreased synthesis of prostaglandins, which have critical established roles in both strain adaptive bone remodeling and fracture healing 3,5,6,8 . However, we cannot conclude that any one of the drugs in the ADVIL variable (ibuprofen, naproxen, celecoxib) is necessarily the most deleterious NSAID for bone health.…”

“…Moreover, the physical activity level of the subjects was not assayed. In addition to the central role of physical activity on stress fracture incidence, previous studies have shown that administration of NSAIDs before or after exercise affects the skeletal consequences 3,5,12,13 . However, the only significant difference between stress fracture and control subjects was BMI, with the ankle sprain cohort having a slightly higher average BMI (30.5 kg/m 2 ) than the stress fracture cohort (27.1 kg/m 2 ) – perhaps indicating an overall higher activity level in the stress fracture subjects 20 .…”

Acetaminophen influences musculoskeletal signaling but not adaptations to endurance exercise training

“…A recent review suggested that NSAIDs has the potential to attenuate or inhibit the osteogenic response to loading. 57 This speculation was based on studies that found indomethacin, NS-398, ibuprofen, and naproxen are detrimental to adaptive bone formation or bone healing. [58][59][60] The mechanism underpinning these changes is thought to be due to the inhibition of COX-2, which is an inducible COX isoform that is increased after exercise or injury.…”

“…A recent review suggested that NSAIDs has the potential to attenuate or inhibit the osteogenic response to loading 57 . This speculation was based on studies that found indomethacin, NS‐398, ibuprofen, and naproxen are detrimental to adaptive bone formation or bone healing 58–60 .…”