Key points

Introduction

Fracture union is a complex process that is intimately related to the biologic and mechanical environments at the fracture site. Improper fracture fixation ranging from undersized intramedullary nails to overstiffened plate constructs can create an unfavorable mechanical environment for fracture union ( Fig. 1 and Fig. 2 ). In the biologic environment, a multitude of cells and molecules are found at fracture sites within hours, and work to provide a framework for fracture repair. There are multiple inflammatory cells found at fracture sites within hours of the injury, and play an influential role in hematoma formation and the early stages of fracture healing within the first 5 days. A multitude of factors influencing fracture union have been suggested including nutritional status; endocrine disorders; smoking; fracture location; fracture energy; fracture pattern; and medications, including steroids, chemotherapy agents, and nonsteroidal anti-inflammatory drugs (NSAIDs). External factors influencing fracture union have come under increasing scrutiny in efforts to reduce the rates of nonunion or delayed union. Particularly, patient nutritional status and smoking status have proven to be influential in fracture healing as a result of altering the molecular environment at the fracture site. Several medications have also come under consideration for their theoretic ability to alter the early inflammatory pathway and the later molecular environment involved in the formation of new bone. For example, there is a theoretic risk of chronic corticosteroid use leading to impaired fracture union because of the inhibition of osteogenic differentiation of mesenchymal stem cells, but this has not been proven in clinical studies.

Atrophic nonunion resulting from an undersized tibial nail.

Fracture union following nonunion surgery with intramedullary nail exchange.

Although there is no standard definition of nonunion, it is generally accepted that nonunion is defined as a lack of complete bone healing within a specified time frame, typically between 6 and 9 months. Nonunion is a known complication of the operative and nonoperative management of fractures. The rate of fracture nonunion has been estimated to be between 5% and 10%. The effects of fracture nonunion are detrimental to the patient and the health care system. Some estimates of tibial shaft nonunions suggest that the median health care cost of nonunion versus union was more than two times greater, despite nonunions representing only 12% of tibial fractures overall. With the increasing focus on patient outcomes and the awareness of external factors that influence fracture union, surgeon- and patient-controlled variables are being increasingly studied. Although smoking is generally accepted as detrimental to fracture healing, a less discussed patient factor is alcohol. Some studies demonstrate an association between alcohol use and impaired fracture healing, with animal studies suggesting that it is a result of the inhibition of osteoblast proliferation.

Specific surgeon-controlled factors are pain-control modalities following operative and nonoperative fracture care. NSAIDs and opioids are two widely used medications to help with pain control in the acute postfracture setting. NSAIDs are commonly used pain medications that target the inflammatory cascade. Because normal fracture healing involves an early inflammatory response, theoretically NSAIDs could interfere with normal fracture healing biology, resulting in a delayed union or a nonunion. Numerous animal models have suggested that NSAIDs can play a role in fracture healing; however, clinical studies have resulted in conflicting recommendations regarding the use of NSAIDs with fractures. Opioids are also frequently prescribed medications by orthopedic physicians and there has been some recent suggestion of opioids influencing fracture union. Although literature is limited on the effect of opioids on fracture union, with no study able to demonstrate causality, there is some suggestion in animal studies and retrospective clinical studies of a negative influence on fracture union. Pain control is an important consideration of patient care, and the treating physicians should be aware of the potential negative side effects of the medications that they are prescribing. To date, there are no defined clinical recommendations regarding a pain management regimen in the setting of fracture with respect to the effects on fracture union. This article reviews the current literature to examine the effects of opioids, alcohol, and NSAIDs on fracture union ( Box 1 , Box 2 , and Box 3 for a summary of key points for each section).

Introduction

Fracture union is a complex process that is intimately related to the biologic and mechanical environments at the fracture site. Improper fracture fixation ranging from undersized intramedullary nails to overstiffened plate constructs can create an unfavorable mechanical environment for fracture union ( Fig. 1 and Fig. 2 ). In the biologic environment, a multitude of cells and molecules are found at fracture sites within hours, and work to provide a framework for fracture repair. There are multiple inflammatory cells found at fracture sites within hours of the injury, and play an influential role in hematoma formation and the early stages of fracture healing within the first 5 days. A multitude of factors influencing fracture union have been suggested including nutritional status; endocrine disorders; smoking; fracture location; fracture energy; fracture pattern; and medications, including steroids, chemotherapy agents, and nonsteroidal anti-inflammatory drugs (NSAIDs). External factors influencing fracture union have come under increasing scrutiny in efforts to reduce the rates of nonunion or delayed union. Particularly, patient nutritional status and smoking status have proven to be influential in fracture healing as a result of altering the molecular environment at the fracture site. Several medications have also come under consideration for their theoretic ability to alter the early inflammatory pathway and the later molecular environment involved in the formation of new bone. For example, there is a theoretic risk of chronic corticosteroid use leading to impaired fracture union because of the inhibition of osteogenic differentiation of mesenchymal stem cells, but this has not been proven in clinical studies.

Atrophic nonunion resulting from an undersized tibial nail.

Fracture union following nonunion surgery with intramedullary nail exchange.

Although there is no standard definition of nonunion, it is generally accepted that nonunion is defined as a lack of complete bone healing within a specified time frame, typically between 6 and 9 months. Nonunion is a known complication of the operative and nonoperative management of fractures. The rate of fracture nonunion has been estimated to be between 5% and 10%. The effects of fracture nonunion are detrimental to the patient and the health care system. Some estimates of tibial shaft nonunions suggest that the median health care cost of nonunion versus union was more than two times greater, despite nonunions representing only 12% of tibial fractures overall. With the increasing focus on patient outcomes and the awareness of external factors that influence fracture union, surgeon- and patient-controlled variables are being increasingly studied. Although smoking is generally accepted as detrimental to fracture healing, a less discussed patient factor is alcohol. Some studies demonstrate an association between alcohol use and impaired fracture healing, with animal studies suggesting that it is a result of the inhibition of osteoblast proliferation.

Specific surgeon-controlled factors are pain-control modalities following operative and nonoperative fracture care. NSAIDs and opioids are two widely used medications to help with pain control in the acute postfracture setting. NSAIDs are commonly used pain medications that target the inflammatory cascade. Because normal fracture healing involves an early inflammatory response, theoretically NSAIDs could interfere with normal fracture healing biology, resulting in a delayed union or a nonunion. Numerous animal models have suggested that NSAIDs can play a role in fracture healing; however, clinical studies have resulted in conflicting recommendations regarding the use of NSAIDs with fractures. Opioids are also frequently prescribed medications by orthopedic physicians and there has been some recent suggestion of opioids influencing fracture union. Although literature is limited on the effect of opioids on fracture union, with no study able to demonstrate causality, there is some suggestion in animal studies and retrospective clinical studies of a negative influence on fracture union. Pain control is an important consideration of patient care, and the treating physicians should be aware of the potential negative side effects of the medications that they are prescribing. To date, there are no defined clinical recommendations regarding a pain management regimen in the setting of fracture with respect to the effects on fracture union. This article reviews the current literature to examine the effects of opioids, alcohol, and NSAIDs on fracture union ( Box 1 , Box 2 , and Box 3 for a summary of key points for each section).

Methods of literature review

A PubMed search was performed to review the current literature regarding fracture union. The search was generated with several combinations of multiple keywords: fracture, union, malunion, heal, healing, opioid, alcohol, and NSAIDs. The following search was used: fracture AND (union OR malunion OR nonunion OR heal OR healing) and (opioid OR alcohol OR NSAIDs). Additionally, the following MeSH terms were used: Fracture Healing [MeSH], Fractures, ununited [MeSH], and Fractures, malunited [MeSH].

The search was limited to peer-reviewed journal articles in the English language published between January 2000 and February 2017. The authors evaluated each article to determine relevance. The reference lists of selected articles were examined for additional relevant articles. Ultimately, the search yielded 40 articles that were deemed relevant.

Opioids and fracture union

Opioids are a mainstay of pain management in the perioperative period among all surgical specialties. Orthopedic patients are no exception, with approximately 80% of fracture patients receiving opioids for analgesia. Given the propensity for orthopedic patients to receive opioids while inpatient and after hospital discharge, an understanding of their effect on fracture healing is absolutely crucial.

The literature focusing on opioids and their effect on fracture union is primarily comprised of animal fracture models and retrospective reviews of human fracture data. The general consensus among the animal fracture models is that opioids impair fracture healing. Chrastil and colleagues demonstrated this with a femoral osteotomy model with rats where one study group received saline and one study group received morphine for 8 weeks. At the conclusion of the study, the rats exposed to morphine demonstrated a decreased rate of fracture callus maturation, ultimately resulting in a weaker fracture callus. The control group fracture callus volume at 8 weeks was lower than that of the morphine-exposed group, suggesting that morphine possibly inhibited fracture callus remodeling and resorption. Following this, Chrastil and colleagues then used their femoral osteotomy rat model to investigate whether opioid-induced androgen deficiency could be responsible for the decreased rate of callus maturation, but the authors failed to support this hypothesis. Chrastil and colleagues ultimately proposed that opioids’ inhibition of fracture callus maturation could be multifactorial, because opioids affect nearly every hypothalamic-pituitary-peripheral gland axis in the human body.

Given the well-documented negative effect of opioids on fracture healing, it is reasonable to consider that antagonism of these same receptors could actually promote fracture healing. Petrizzi and colleagues used a common opioid antagonist, naloxone, and a bicortical drill hole model in a group of sheep to investigate this concept further. The researchers drilled a bicortical hole in the left metacarpus in a group of sheep and divided the sheep into various study groups. Each group received saline, calcium gluconate, naloxone, or both naloxone and calcium gluconate for 4 weeks. Monitoring bone healing radiographically and histologically, the group determined there was significantly faster healing in the naloxone and naloxone plus calcium gluconate group in comparison with the control group and calcium gluconate group. The naloxone plus calcium gluconate group also healed significantly faster the naloxone only group. The authors concluded that naloxone enhances mineralization and remodeling in the fracture callus of sheep, and this effect is potentiated by the concurrent administration of calcium gluconate. These results suggest naloxone could be used as a potential pharmacologic treatment of nonunion, or prophylaxis for patients where this is of considerable risk.

The human studies investigating the effect of opioids on fracture healing are retrospective chart reviews examining different factors that influence fracture healing. Although the animal models clearly suggest a direct negative impact of opioids on fracture healing, the human data are not as forthright. Although Bhattacharyya and colleagues calculated an odds ratio of 2.7 for opioid use and nonunion of humeral shaft fractures, the authors actually suggest this to be protopathic bias, where the use of analgesic medication is essentially a marker for a painful nonhealing fracture. More recently, large retrospective reviews by Antonova and colleagues and Zura and colleagues examining factors affecting fracture nonunion demonstrated a propensity for nonunion in the patients using opioids for pain management, but given the retrospective nature of these studies, causality cannot be further investigated. By and large, the human data on the effect of opioids on fracture healing are lacking, and further research in this field is necessary to properly guide perioperative analgesia in these patients.