A Disunion of the Literature - NSAIDs and Fracture

The Gist:  Currently, practice and literature are divisive with regard to issues of non-steroidal anti-inflammatory medications (NSAIDS) and bone healing in fractures; however, analgesic dosed NSAIDs are probably ok in the acute fracture process in most patients.  Check out this open access article by Yates et al.

The Case:  A 11 y/o male presented to Janus General with left forearm edema and deformity after falling during a basketball game.  Imaging demonstrated a non-displaced, transverse radius fracture with less than ten degrees of volar angulation. The patient received ibuprofen, was placed in a splint, and follow up with orthopedics was arranged.  Later, the orthopedist instructed me not to give NSAIDs to patients with fractures "because they delay healing."  I was marginally acquainted with the controversy from reading these bits of FOAM (Free Open Access Medical education) previously: The Trauma Professional and Jacobi EM's take, but I was startled enough by the physician's rigid statement of fact to review the literature myself.

Why the worry?

• Non-union is a feared, delayed complication of fracture and is estimated to occur in ~1% of long bone fractures although this rate is higher in other fractures and influenced by individual factors (1).
• Studies of NSAIDs in fracture healing conducted in rats tend to show delayed fracture healing, delayed callus formation, and increased prevalence of non-union -see Table 1 in this article (2,3).  
• The biologic plausibility - The initially inflammation generated by a fracture plays a role in creating the environment for bone healing (5).  NSAIDs inhibit cyclo-oxygenase (COX), decreasing the presence of some prostaglandins (2). Prostaglandins such as PGF2A and PGE2 aid in bone healing by stimulating osteoblasts.  These prostaglandins are also thought to play a role in angiogenesis necessary for bone repair/regeneration as well as bone metabolism (3).  Thus, COX inhibition and interference with these cytokines may interrupt the body's natural way of repairing itself.

The Human Literature:  Oftentimes, animal studies and in vitro experiments don't translate into how things work in the human body and it appears this is the case with NSAIDs and fracture, as the data is a wash.  Why might this be?

• No prospective RCTs with sufficient power have been conducted that reflect NSAIDs dosed for analgesia in patients with acute fracture.  
• Clinical practice contains far more variables than a well designed laboratory study, thus confounding the data.  For example, mechanism of injury, smoking and glycemic control can affect fracture healing rates but these vary individually (1).  
• Studies look at various kinds of fractures that have disparate expected rates of non-union (ex: post-op spinal surgery has 10-15% rates of non-union vs 1-5% of long bone fractures) (4).
• Retrospective studies examining NSAIDs and delayed healing often involved routine, protracted dosing of NSAIDs or may have been more common in patients with more complicated fractures or signs of complications, as they consumed more NSAIDs.  

This free, full-text article by Wheeler et al summarizes the human studies with NSAIDs in fracture healing in Table 2 on the second page.  Below are some of the highlights from the literature:

DePeter KC et al.  Retrospective study of pediatric patients without high-risk systemic features for malunion treated for acute fracture of a high-risk bone (femur, tibia, scaphoid, humerus, 5th metatarsal) in the emergency department who received ibuprofen or a prescription for ibuprofen (42%) compared with those who did not.  They found no association for delayed or malunion OR 0.8 (0.4-1.8).

• Limitation: like many retrospective studies, it is not clear that patients that were prescribed ibuprofen actually took this medication. Conversely, patients may have taken ibuprofen without a prescription.

Burd et al Retrospective, increased incidence of non-union in NSAID group (26% vs 7%, p = 0.004) and those with worse fractures.

• Note: The patients in this study received indomethacin 25 mg TID x 6 weeks, which is not consistent with our acute pain dosing (they were looking at inhibiting heterotopic bone formation).

Bhattacharyya et al  Retrospective database review, looking at patients who filled prescriptions for an NSAID in the 90 days after humeral shaft fracture.  The study only showed a significant difference in non-union in patients exposed to NSAIDS between 61-90 days (RR 3.9, 95%CI 2.0–6.2)

• Limitation: NSAID use was neither quantified nor specified by type.  Of note, this cohort of 9995 patients predominantly included older adults (mean age = 77)

Adolphson et al.  n=42, RCT with piroxicam in post-menopausal women with distal radius fractures with dorsal displacement (Colles), no delay in fracture healing.

Dodwell et al - meta-analysis, inconclusive.  The pooled odds ratio for nonunion was significantly higher in patients exposed to NSAIDs when the heterogeneous studies of variable quality were analyzed together (OR 3.0, 95% CI 1.6-5.6). The higher quality studies alone did not demonstrate an increased odds of non-union (OR 2.2, 95% CI 0.8-6.3).

• Limitations: Case-control and cohort studies only, long bone and spine surgeries pooled together, variable NSAID and dosing.

What I've taken away for my practice:

• Ensure adequate immobilization of fractures to mitigate pain (5).
• Provide analgesia to patients using a pain algorithm, which will continue include NSAIDs (such as ibuprofen 400 mg) or acetaminophen as needed for pain in patients with fracture. 
• Consider the individual patient and factors that may put them at risk for impaired healing (high-risk fracture, osteoporosis, smoking status, diabetes, etc).
• Encourage patients to use the lowest effective dose of NSAIDs for the shortest period of time as the data suggests that higher doses of NSAIDs may be associated with delayed healing (4*,6).
• Avoid aggravating colleagues and continuing dialogue on this evolving topic, when possible, by factoring in which orthopedist is on-call when prescribing NSAIDs. 

References:

1.  Howe A.  General principles of fracture management: Early and late complications.  UpToDate.

2.  Pountos I, et al.  Do Nonsteroidal Anti-Inflammatory Drugs Affect Bone Healing? A Critical Analysis. ScientificWorldJournal. 2012; 2012: 606404

3.  Kurmis et al. The effect of nonsteroidal anti-inflammatory drug administration on acute phase fracture-healing: a review. J Bone Joint Surg Am. 2012 May 2;94(9):815-23. doi: 10.2106/JBJS.J.01743. 

4.  Reuben SS.  High dose nonsteroidal anti-inflammatory drugs compromise spinal fusion. Can J Anaesth. 2005 May;52(5):506-12.  *note: this study is authored by an individual who had 21 other publications retracted due to falsified studies, so findings should be taken with a grain of salt.

5.  Menkes J.  Tintinalli's Emergency Medicine.  7th ed. New York: McGraw Hill Medical. 2011.  p.1789
6. Dodwell ER, et al.  NSAID exposure and risk of nonunion: a meta-analysis of case-control and cohort studies.
Calcif Tissue Int. 2010 Sep;87(3):193-202. 
DePeter KC, Blumberg SM, Dienstag Becker S, Meltzer JA. Does the Use of Ibuprofen in Children with Extremity Fractures Increase their Risk for Bone Healing Complications? The Journal of emergency medicine. 2016. [pubmed]