Can we use NSAID's in patients with fractures?

The topic of Non-steroidal Anti-inflammatory (NSAID) use in fracture healing has been a lively source of discussion in Orthopaedic literature, particularly in recent years. Common teaching for over a decade has often been that, despite their analgesic and anti-inflammatory properties, the use of NSAIDs should be minimized in fracture care due to a proposed causation of delayed healing. The pathophysiology behind this is that following a fracture, local release of prostaglandins occurs early as a consequence of the acute aseptic inflammatory response, and cyclo-oxygenase-2 plays a critical role in this generation and the consequent induction of osteoblasts that occurs. NSAIDs, being cyclo-oxygenase inhibitors, therein inhibits the inflammatory response necessary for bone healing. Additionally, more recent studies have identified other deleterious effects on the fracture healing cascade, as with diclofenac’s inhibition of BMP-7 (an anabolic hormone affecting bone growth) signaling in a mouse model [1].

However, clinical and bench research alike have demonstrated recent conflicting conclusions of the risks of NSAID use in the acute phase of fracture healing. Hernandez et al identified United Kingdom General Practice Research Dabase patients with fracture-healing complications (delayed union, nonunion, or malunion) between 1988 and 2004, and when matched against control patients with normal healing, determined that NSAID use even before (within 12 months) of the fracture were associated with a  higher odds of fracture-healing complications (adjusted OR = 2.6, CI: 2.1-3.2) [2]. A systematic review of the literature by Pountos et al analyzing in vitro animal and clinical studies in the field revealed much conflicting data, but suggested that NSAIDs should be viewed as a risk factor for bone healing impairment [3]. In a review of 44 articles, predominantly assessing animal data, Chen et al discussed their findings that short-term, lwo-dose use of NSAIDs and CoX-2 inhibitors is inhibitory in cases of injury involving bony healing [4]. Kidd et al evaluated a rat model for ulnar stress fractures and reported a potential compromise of healing by both COX-2 inhibitors and non-selective NSAIDs [5]. However, additional studies in recent years have contrasted the aforementioned conclusions. Cappello et al saw no inhibitory effects of ketorolac on early juvenile rat fracture healing and suggested that NSAIDs may be reasonable to use for analgesia in children with long bone fractures [6]. Another systematic literature review by Kurmis et al noted that although increasing evidence from animal studies suggests that COX-2 inhibition suppresses early fracture healing, but in vivo studies with humans have not provided such robust evidence to completely contraindicate its use in fractures [7].

Take-away points:
    1) Most biochemical and animal studies demonstrate an inhibition of the fracture healing cascade by NSAIDs
    2) Clinical (observational) studies report conflicting results on whether NSAIDs inhibit bony healing, and whether their use should be heeded or encouraged
    3) Randomized, controlled trials evaluating this topic would be helpful… but have not happened yet
    4) Clinical preference may guide decision to use NSAIDs for analgesia in the setting of fracture
 My opinion: There is enough evidence to convince me that NSAIDs could have a deleterious effect on my patient’s fracture healing, in an absence of any potential for enhancing bony healing (or being of use for anything in this clinical scenario beyond analgesia). Thus, I would not chance it, and stick to other forms of pain control that do not have the stigma of NSAIDs in this situation!

 [1] Spiro AS, Beil FT, Baranowsky A, Barvencik F, Schilling AF, Nguyen K, Khadem S, Seitz S, Rueger JM, Schinke T, Amling M. BMP-7-induced ectopic bone formation and fracture healing is impaired by systemic NSAID application in C57BL/6-mice. J Orthop Res. 2010 Jun; 28(6): 785-91.
 [2] Hernandez RK, Do TP, Critchlow CW, Dent RE, Jick SS. Patient-related risk factors for fracture-healing complications in the United Kingdom General Practice Research Database. Acta Orthop. 2012; 83(6): 653-60.
 [3] Pountos I, Georgouli T, Calori GM, Giannoudis PV. Do nonsteroidal anti-inflammatory drugs affect bone healing? A critical analysis. Scientific World Journal. 2012; Epub.
 [4] Chen MR, Dragoo JL. The effect of nonsteroidal anti-inflammatory drugs on tissue healing. Knee Surg Sports Traumatol Arthrosc. 2013; 21(3): 540-9.
  [5] Kidd LJU, Cowling NR, Wu AC, Kelly WL, Forwood MR. Selective and non-selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna. J Orthop Res. 2013; 31(2): 235-42.
 [6] Cappello T, Nuelle JA, Katsantonis N, Nauer RK, Lauing KL, Jagodzinski JE, Callaci JJ. Ketorolac administration does not delay early fracture healing in a juvenile rat model: a pilot study. J Pediatr Orthop. 2013; 33(4): 415-21.
 [7] Kurmis AP, Kurmis TP, O’Brien JX, Dalen T. The effect of nonsteroidal anti-inflammatory drug administration on acute phase fracture-healing: a review. J Bone Joint Surg Am. 2012; 94(9): 815-23.

submitted by Dr. Bryan Saltzman