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NSAIDs And Bone Healing: What The Research Reveals

In light of increasing concerns about opioids and drug-drug interactions, these authors examine the literature on NSAIDs, and suggest that appropriate short-term dosing of NSAIDs can play a viable adjunctive role in post-op pain management.  

The evidence supporting multimodal pain approaches has continued to increase throughout the literature, especially in recent years. This approach allows physicians to use medications with improved safety profiles, fewer side effects such as physical dependence and lower costs for pain control.

The American Pain Society published guidelines in 2016 recommending non-opioid medications including acetaminophen and/or non-steroidal anti-inflammatory drugs (NSAIDs) as part of a multimodal approach to postoperative pain management in orthopedic patients without contraindications.1 When patients combine acetaminophen and/or NSAIDs with opioid use, they often experience significantly less pain and opioid consumption decreases in comparison with opioid use alone.1 Owing to their ability to synergistically improve pain, NSAIDs reduce concurrent narcotic requirements and shorten the overall hospital length of stay.2–4 A review by Kurmis and colleagues noted that most of the literature suggests using an NSAID regimen for a short duration can safely and effectively supplement other types of pain control after fractures without a significantly higher risk of sequelae related to disrupted healing.2

Paradoxically, many foot and ankle surgeons continue to eschew the utilization of NSAIDs in the perioperative and postoperative periods, instead electing to rely primarily on opioid medications—such as codeine, hydrocodone, oxycodone (Oxycontin, Purdue Pharma) and oxycodone/acetaminophen (Percocet, Endo Pharmaceuticals)—for pain control. This rationale stems from the inconsistent evidence regarding NSAIDs and impairment of bone healing in historical animal-based studies.

However, in a study of 97 patients, Bot and colleagues noted that patients who took more opioids reported having more intense pain after fracture surgery.5 Helmerhorst and coworkers noted, in a study of 60 patients who had ankle fractures, that those who used non-opioid medication reported less pain than those who used opioids.6 Finally, in a study of 306 patients who had hip and ankle fractures, Lindenhovius and colleagues concluded that physicians prescribed opioids at a higher rate for American patients in comparison to Dutch patients.7

What we have clearly determined is that increasing opioid intake is consistently associated with increasing levels of pain and possibly opioid-induced hyperalgesia without any demonstrable improvements to patients’ postoperative level of pain or satisfaction.5–7 With opioids claiming 92 lives every day in the United States, it is clear a pertinent review of the facts regarding NSAIDs and human bone healing is needed to better inform physicians on the available evidence, and guide clinical decision making.8  
    
What You Should Know About The Mechanism Of Action And Effects Of NSAIDs

Since their introduction in 1899, NSAIDs have become among the most widely utilized medications for the treatment of musculoskeletal pain. The prevailing theory for their mechanism of action is the inhibition of the cyclooxygenase (COX) pathway, which subsequently prevents the generation of the potent inflammatory end products: prostaglandins, leukotrienes and other related compounds.2,9 The initial trigger of these end products is exposure to a noxious stimulus such as a fracture. These mediators are responsible for producing pain, inflammation, swelling and fever, and are essential in orchestrating early events in bone healing.2,10,11

The role of prostaglandins is multifactorial as prostaglandins will either promote osteoclastic activity, thereby increasing bone resorption, or they will activate osteoblastic activity, which will increase bone production.12 The COX modulated prostaglandins E2 (PG-E2) and F2a promote active bone formation and their effect in bone metabolism has had extensive study.2,13 During the first two weeks of fracture callus formation, PGE-2 is released locally with rates falling drastically by day 21 and then returning to near normal levels by week six of healing.14,15 Animal studies suggest that inhibition of PG-E2 may reduce bone density and stiffness, and increase fibrous tissue formation in healing.16,17 These effects are at their most significant during the first two weeks of bone callus formation and research has shown these effects impair the transition of soft callus to hard callus.18

Authors have widely reported the controversial use of NSAIDs following fractures since 1976 with Bo and colleagues relating impaired healing on rats using indomethacin, and Sudmann and Hagen finding a similar result in a human using indomethacin.10,19 The COX mechanism of action alone does not sufficiently explain all the anti-inflammatory actions of NSAIDs. However, traditionally, NSAIDs have been categorized into non-selective COX inhibitors and selective COX-2 inhibitors, each of which provide analgesia and reduce inflammation.

Despite their commonality, each COX isoenzyme is unique. The COX-1 isoenzyme is constitutive and produced ubiquitously at a constant rate under normal physiologic conditions. Conversely, the COX-2 isoenzyme is inducible under certain conditions, including the inflammation resulting from trauma. Here in particular, the role of the COX-2 isoenzyme with regard to the production of human osteoblasts and, by extension, fracture healing have occurred.2 Interestingly, researchers have also proposed a controversial COX-3 isoenzyme, although its pharmalogical relevance, if any, currently remains unclear.

Note that both non-selective and selective COX-2 inhibitors are not without adverse effects. For non-selective COX-1 inhibitors, serious gastrointestinal risk with chronic use remains a concern.20 To overcome these negative gastrointestinal effects associated with the inhibition of COX-1, we saw the emergence of selective COX-2 inhibitors. However, for these selective inhibitors of the inducible COX-2 enzyme following injury, cardiovascular risk and the inhibition of human osteoblasts remain concerns.21 The inhibition of COX enzymes will either reversibly or irreversibly inhibit prostaglandin synthesis, especially in the acute inflammatory phase.22 The role of NSAIDs immediately following a fracture has raised theoretical concerns that NSAIDs will slow the healing process, thereby increasing the risk of delayed union or nonunion.16,23

Do NSAIDs Impair Bone Healing?

The impetus driving pain management away from a multimodal approach stems from a large body of in vitro and in vivo animal studies that demonstrate NSAIDs impair bone healing.15,24–26
Lindholm and Tornkvist studied ibuprofen in rats, and found that bone formation was inhibited on endosteal surfaces of the tibia, which diminished the amount of cortical bone.15 O’Connor and coworkers compared the effects of ibuprofen and rofecoxib on rats with healing fibula osteotomies.24 They noted nonunion in five of 26 animals treated with rofecoxib in comparison to one non-union out of 24 in the placebo group and one nonunion in 30 rats using ibuprofen.24 In a study of 296 mice, Mullis and colleagues found indomethacin, celecoxib, rofecoxib, ibuprofen and ketorolac (Tramadol, Roche) had no significant effects on fracture healing.25

These studies have provided greater understanding in regard to the histology and physiology of bone healing.15,24–26 However, extrapolating data to apply in the clinical setting is daunting as the results are extremely variable.

It is notable that most of the studies reporting impaired bone healing with NSAIDs are of lower quality evidence than those that refute the incidence of clinically impaired bone healing.27–30 Furthermore, the lower quality studies are of animal species more distant to humans (rodents) in comparison to species that are more similar to humans (goats and dogs), which report minimal to no impact of NSAIDs on bone healing.17,31,32 In humans, other factors including comorbid conditions (peripheral vascular disease, diabetes, smoking), fracture stability and location (axial versus appendicular skeleton) as well as concurrent medications may all potentially impact osseous healing. These effects could have more significant impacts on the body’s intrinsic ability for osseous repair in comparison to COX inhibition alone although prior studies have failed to satisfactorily incorporate or assess these potential confounders. The controversial use of NSAIDs owing to osseous concerns thus perfectly illustrates a fallacy of causation.

In 2016, Marquez-Lara and colleagues examined research quality in a systematic review of studies looking at NSAIDs and bone healing, and found significant variability in study designs that have yielded inconsistent results.27,29,30 The review points out that one must take into consideration various factors in studies such as the bioavailability of each individual NSAID as well as dose, timing and length of exposure. Most animal study models involved NSAIDs for a prolonged period of time, often greater than six weeks, which opposes the clinical application that often consists of a short duration in the postoperative patient.

One study found that COX-2 specific drugs inhibit fracture healing more than non-specific NSAIDs but this was related to the duration of the treatment.33 Following discontinuation of the treatment, PG-E2 levels were gradually restored to levels similar to that of control patients, which highlights the possibility of reversing the potentially harmful side effects as they relate to bone healing.Looking deeper into the studies, when comparing ibuprofen to indomethacin following withdrawal of the agent, only the reversibility of indomethacin occurred.34 The explanation for this may reflect a lack in dose equivalency when comparing the two agents.

Many studies often examine the effects of the most potent NSAIDs at dosages that exceed the typical prescribed amount. Ketorolac and indomethacin are two such medications. Before using those agents, one should carefully consider their routine and protracted use in the postoperative patient. Despite these warnings, trending evidence suggests that exposure to NSAIDs of fewer than 14 days at a normal dose did not increase the risk of nonunion.35

In Conclusion

In the current state of practice in which the standard of care relies upon evidence-based medicine, there is no clear evidence that allows surgeons to advocate for or against the use of NSAIDs following orthopedic procedures. Using all available evidence in animal studies, we can conclude that NSAIDs may affect the early phases of bone healing. However, this is dependent upon the type, timing, dose and length of exposure.

With that consideration, it is unclear how NSAID use may interact with other comorbid conditions that affect bone healing and one must take the patient’s overall health into consideration. Furthermore, one may not accurately extrapolate the results obtained with the use of NSAIDs in the axial skeleton to the appendicular skeleton.

Randomized prospective trials in humans are needed to form a consensus regarding the use of NSAIDs in the postoperative orthopedic patient. Although prospective studies on NSAIDs and bone healing in the foot and ankle have been presented at national conferences including the American College of Foot and Ankle Surgeons Annual Scientific Conference, after more than half a decade, none of the abstract presentations have matured into full text journal publications.

With the exclusion of very few, the majority of NSAIDs are some of the most effective drugs used to treat postoperative pain. With a review of the most current literature, it appears that short-duration NSAID use in a multimodal approach to pain control of the postoperative orthopedic patient does not appear to have irreversible effects on bone healing in the low to moderate risk patient. However, one should avoid NSAID use in patients at high risk for impaired bone healing.

Dr. Rogers is the Research Director at Memorial Healthcare System in Hollywood, Fla. She is a Fellow of the American College of Foot and Ankle Surgeons.

Dr. Joseph is an Associate Professor and the Chairman of Podiatric Medicine and Radiology at the Dr. William M. Scholl School of Podiatric Medicine at Rosalind Franklin University of Medicine and Science. He is a Fellow of the American College of Foot and Ankle Surgeons.

Dr. Rushing is a second-year resident at Westside Regional Medical Center in Plantation, Fla.

References
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13.     Pountos I, Georgouli T, Blokhuis TJ, Pape HC, Giannoudis PV. Pharmacological agents and impairment of fracture healing: what is the evidence? Injury. 2008;39(4):384-94.
14.     Simon AM, Manigrasso MS, O’Connor JP. Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner Res. 2002;17(6):963-76.
15.     Lindholm TS, Tornkvist H. Inhibitory effect on bone formation and calcification exerted by the anti-inflammatory drug ibuprofen. An experimental study on adult rat with fracture. Scand J Rheumatol. 1981;10(1):38-42.
16.     Brown KM, Saunders MM, Kirsch T, Donahue HJ, Reid JS. Effect of COX-2 specific inhibition on fracture-healing in the rat femur. J Bone Surg Am. 2004;86(1):116-23.
17.     Goodman SB, Ma T, Mitsunaga L, Miyanishi K, Genovese MC, Smith RL. Temporal effects of a COX-2 selective NSAID on bone in growth. J Biomed Mater Res A. 2005;72(3):279-87.
18.     Endo K, Sairyo K, Komatsubara S, Sasa T, Egawa H, Ogawa T, Yonekura D, Murakami R, Yasui N. Cyclooxygenase-2 inhibitor delays fracture healing in rats. Acta Orthop. 2005;76(4):470-4.
19.     Sudmann E, Hagen T. Indomethacin-induced delayed fracture healing. Arch Orthop Unfallchir. 1976;85(2):151-4.
20.     Ofman JJ, MacLean CH, Straus WL, Morton SC, Berger ML, Roth EA, Shekelle P. A metaanalysis of severe upper gastrointestinal complications of nonsteroidal antiinflammatory drugs. J Rheumatol. 2002;29(4):804-812.
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22.     Wixted JJ, Fanning P, Rothkopf I, Stein G, Lian J. Arachidonic acid, eicosanoids and fracture repair. J Orthop Trauma. 2010 Sep;24(9):539-42.
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Additional References
36.     Altamn RD. Neutrophil activation: an alternative to prostaglandin inhibition as the mechanism of action for NSAIDs. Semin Arthritis Rheum. 1990;19(4 Suppl 2):1-5.       
37.     Nunamaker DM. Experimental models of fracture repair. Clin Orthop Relat Res. 1998; (355)(Suppl):S56-65.
38.     Lumawig JM, Yamazaki A, Watanabe K. Dose-dependent inhibition of diclofenac sodium on posterior lumbar interbody fusion rates. Spine J. 2009.;9(5):343-9.
39.     Adolphson P, Abbaszadegan H, Jonsson U, Dalen N, Skoberg 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):127-30.
40.     Solomon DH. UpToDate. NSAIDs: Pharmacology and mechanism of action. Available at https://www.uptodate.com/contents/nsaids-pharmacology-and-mechanism-of-action?search=NSAIDs%20mechanism%20of%20action&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. Accessed February 2018.
41.     Helmerhorst GT, Zwiers R, Ring D, Kloen P. Pain relief after operative treatment of an extremity fracture: a noninferiority randomized controlled trial. J Bone Joint Surg Am. 2017;99(22):1908-15.

Editor’s note: For further reading, see “A Guide To Drug–Drug Interactions In Podiatry” in the August 2011 issue of Podiatry Today.

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Diana E. Rogers, DPM, MS, FACFAS, Robert M. Joseph, DPM, PhD, FACFAS, and Calvin J. Rushing, DPM
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