SLR - May 2019 - Nicole Naz Mehr

Effect of NSAIDs on Bone Healing Rates: A Meta-Analysis

Reference: Wheatley BM, Nappo KE, Christensen DL, Holman AM, Brooks DI, Potter BK. Effect of NSAIDs on Bone Healing Rates: A Meta-Analysis. J Am Acad Orthop Surg. 2018 Sep 26; 1–7.

Scientific Literature Review

Reviewed By: Nicole Naz Mehr, DPM
Residency Program: Truman Center Lakewood, Kansas City, MO Medical

Podiatric Relevance: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in the perioperative period for pain relief. They are often used in combination with opioids for multimodal analgesia. Most NSAIDs' mechanism of action includes inhibition of cyclooxegnase -1 (COX-1) and cyclooxygenase -2 (COX-2) pathways in the synthesis of prostaglandins. Prostaglandins play a critical role in bone formation. There is a lack of consensus in literature on the effect of NSAID exposure and bone healing. The purpose of this meta-analysis was to determine the risk of delayed or nonunion in the setting of fracture, osteotomy or fusion surgery. Secondary outcome measures included effects exposure dose, duration and what the effects were in the pediatric versus adult population.

Methods: A meta-analysis was performed, including all relevant randomized control trials and cohort and case-control studies from January 1990 to October 2016. Outcomes of interest included delayed union, nonunion and pseudoarthrosis. These were not differentiated during final analysis. The minimum length of follow-up was six months. Studies with zero events in both the exposed and nonexposed groups were excluded. Separate subgroup analysis was performed in studies of pediatric and adult patients that involved a low dose or short duration of NSAID treatment. Low dose was defined as < 125 mg/d of diclofenac, 150 mg/d of indomethacin or 120 mg/d of ketorolac. Short duration was defined as < 2 weeks of treatment.

Results: Sixteen studies were considered for final analysis with a total of 15,242 bones evaluated. Of these, 3,283 were exposed to NSAIDs, and 11,959 were not. A pooled analysis was performed with findings of 512 cases of delayed union or nonunion, of which 226 had been exposed. Overall findings were that NSAID exposure led to increased incidence of delayed or nonunion. A subgroup analysis of four studies involving only pediatric patients was performed with a total of 2,018 bones, of which 1,181 were exposed to NSAIDs. A total of 37 cases of delayed or nonunion were reported, of which 13 had been exposed to NSAIDs. No adverse effect with NSAID exposure was noted in pediatric patients. A subgroup analysis of four studies of adult patients with low dose or short duration of treatment was performed with a total of 1,109 bones, of which 510 were exposed to NSAIDs and 599 were not. A total of 98 cases of delayed or nonunion were reported, of which 52 had been exposed to NSAIDs. No increased risk of delayed or nonunion was found as a result of low dose or short duration exposure to NSAIDs.

Conclusions: There was a statistically significant increased risk of nonunion and delayed union with long-term exposure of adult patients to NSAIDs. No increased risk was seen in the pediatric population or with short duration and low-dose exposure. Limitations of this meta-analysis include a lack of studies on the young adult population and heterogeneity among included studies, which was addressed through use of a random-effects model. Based on the findings from this meta-analysis, NSAIDs should be avoided in patients at increased risk of delayed or nonunion. 

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