Where Are We With NSAIDs And Postoperative Bone Healing?

The opioid epidemic brings to light the very real and challenging nature of post-operative pain control in our surgical and non-surgical patients. Multimodal pain management includes non-pharmacologic therapy such as ice, physical therapy and acupuncture in addition to non-opioid pharmacologic therapies including acetaminophen, anticonvulsants, antidepressants, muscle relaxants and non-steroidal anti-inflammatory drugs (NSAIDs). However, as a result of decreasing opioid use for pain management in our patients, we have had a proportional increase in NSAID use. But what do we really know and understand about NSAIDs and bone healing complications? 

A closer look at fracture healing demonstrates cytokines and growth factors that are released both locally and systemically. This induces a mitogenic and osteogenic effect on osteoprogenitor cells. The formation of new blood vessels, in association with further growth factor and prostaglandin production, promotes differentiation of mesenchymal stem cells toward chondrogenic or osteogenic cells. This in turn becomes what we consider hard callus. Finally, this is followed by a remodeling phase with resorption and new bone formation.^1,2 

Non-steroidal anti-inflammatory drugs provide anti-inflammatory, antipyretic, analgesic and antithrombotic effects. They work through the inhibition of cyclooxygenase (COX)-1 and COX-2. The COX-1 and COX-2 enzymes play important roles in the synthesis of prostaglandin. Remember, that in order to have a normal bone healing process, prostaglandin production promotes chondrogenic and osteogenic cell formation. Thus, by inhibiting COX enzymes, we are inhibiting prostaglandin production, which in theory would inhibit bone healing. But is this what really happens?^1,2

What Does The Literature Say?

The literature is divided in regard to bone healing and concomitant NSAID use. Both animal and human studies demonstrate mixed results on whether we are inhibiting normal bone formation with COX inhibition. There have been various studies that demonstrate NSAIDs are safe following fracture fixation and spinal fusions without negative effects on bone healing.^3-6 On the contrary, there have also been human studies suggesting delayed healing and nonunions with the use of NSAIDs after various orthopedic procedures.^7-10 In 2014, Jeffcoach and colleagues found that patients with long bone fractures who received NSAIDs in the postoperative period were twice as likely to develop a nonunion/malunion or infection.¹⁰ That said, the existing literature on post-op NSAID use has primarily focused on orthopedic and spine procedures. Research is sparse with regard to NSAID use after foot and ankle surgery. 

Foot and ankle reconstruction procedures have been known to be painful and require lengthy recoveries. To increase the potential for osseous healing and minimize patient risk, further investigation is necessary to study the inherent side effects of NSAIDs on foot and ankle osteotomies and fusions. In 2019, Hassan and Karlock performed a retrospective study on elective foot and ankle osteotomies. They found that short-term use of oral ibuprofen and ketorolac did not demonstrate any association with nonunion.¹ 

Due to the extensive pharmaceutical options including COX inhibitors and other NSAIDs that could all potentially inhibit various aspects of bone healing, we need more head-to-head comparative studies. Is ketorolac better than ibuprofen? Which drug is better post-operatively: naproxen or piroxicam?

Our daily perioperative management of surgical and non-surgical foot and ankle patients is challenging. When it comes to NSAID use, we cannot take the potential risks lightly. More research is necessary to inform physicians how to adequately manage these risks.

Dr. Pirozzi is a Fellow of the American College of Foot and Ankle Surgeons (ACFAS) and serves as Vice President for ACFAS Region 2. She is currently practicing in Phoenix, Ariz. 

References 

1. Hassan MK, Karlock LG. The effect of post-operative NSAID administration on bone healing after elective foot and ankle surgery. Foot Ankle Surg. 2019. doi: 10.1016/j.fas.2019.05.016.

2. Marquez-Lara A, Hutchinson ID, Nunez F Jr, Smith TL, Miller AM. Nonsteroidal anti-inflammatory drugs and bone-Healing. J Bone Joint Surg. 2006;4(3):e4. 

3. Davis TR, Ackroyd CE. Non-steroidal anti-inflammatory agents in the management of Colles’ fractures. Br J Clin Pract. 1988;42(5):184-189.

4. Adolphson P, Abbaszadegan H, Jonsson U, Dalen N, Sjoberg HE, Kalen S. No effects of piroxicam on osteopenia and recovery after Colles’ fracture. A randomized, double-blind, placebo-controlled, prospective trial. Arch Orthop Trauma Surg. 1993;112(3):127-130.

5. Pradhan BB, Tatsumi RL, Gallina J, Kuhns CA, Wang JC, Dawson EG. Ketorolac and spinal fusion: does the perioperative use of ketorolac really inhibit spinal fusion? Spine (Phila Pa 1976). 2008;33(19):2079-2082.

6. Bhattacharyya T, Levin R, Vrahas MS, Solomon DH. Nonsteroidal anti-inflammatory drugs and nonunion of humeral shaft fractures. Arthritis Rheum. 2005;53(3):364-367.

7. Park SY, Moon SH, Park MS, Oh KS, Lee HM. The effects of ketorolac injected via patient controlled analgesia postoperatively on spinal fusion. Yonsei Med J. 2005;46(2):245-251.

8. Burd TA, Hughes MS, Anglen JO. Heterotopic ossification prophylaxis with indomethacin increases the risk of long-bone nonunion. J Bone Joint Surg Br. 2003;85(5):700-705.

9. Giannoudis PV, MacDonald DA, Matthews SJ, Smith RM, Furlong AJ, De Boer P. Nonunion of the femoral diaphysis. The influence of reaming and non-steroidal anti-inflammatory drugs. J Bone Joint Surg Br. 2000;82(5):655-658.

10. Jeffcoach DR, Sams VG, Sams VG, et al. Nonsteroidal anti-inflammatory drugs’ impact on nonunion and infection rates in long-bone fractures. J Trauma Acute Care Surg. 2014;76(3):779-783.