WHAT IS THE ROLE OF NUTRITIONAL OPTIMIZATION IN THE TREATMENT OF NONUNIONS?
“The process of increasing a patients' functional reserve in anticipation for surgery is referred to as prehabilitation.”5 Prehabilitation is designed to improve the overall wellness of the preoperative patient in an effort to maximize surgical results and postoperative recovery. Fortunately, the surgical management of fracture nonunion is typically a “pseudoelective” procedure. The patient and surgeon have time to maximize success through a process of prehabilitation aimed at increasing the likelihood of surgical success while avoiding local and systemic complication.
Prehabilitation should be multidisciplinary and be individualized to the specific patient and anticipated surgery. Malnutrition is a very significant contributor to surgical complications and requires correction before nonunion reconstruction. Surgery induces a catabolic state that exceeds the biologic reserve in the malnourished host manifesting in local and/or systemic complication as well as compromised surgical outcomes.
Chung et al6 in a study evaluating outcomes of 12,373 geriatric hip fracture patients determined that malnutrition was associated with a greater incidence of major postsurgical complication, longer hospital stay, hospital re-admission, re-operation, and mortality. Moloney et al7 found similar findings in hypoalbuminemic geriatric patients with distal femur fractures reporting an increase in infection, nonunion, length of hospital stay, and 1-year mortality. The prevalence of malnutrition in orthopaedic and trauma patients is significant. Ihle et al using the Nutritional Risk Screening (NRS 2002) method determined that more than 20 percent of trauma and orthopaedic patients were at risk for malnutrition.8 Not surprisingly, prolonged hospital stay and an increased rate of complication was significantly higher in the malnourished cohort. The malnourished patient with nonunion deserves nutritional prehabilitation that often includes consultation and treatment from a licensed dietician before surgical reconstruction. Typical recommendations include protein consumption 1–2 gm/kg/d. Furthermore, adequate vitamin and mineral consumption is prescribed especially zinc, iron, vitamins C and D. Correction of malnutrition will provide the patient with the building blocks necessary for bone and wound healing as well as boost the immune system to prevent infectious complication after nonunion surgery. Furthermore, immune nutrition (arginine ± glutamine, omega 3 fatty acids, and nucleotides) should be considered in the presurgical nonunion patient. This nutritional supplementation stimulates the nitric oxide pathway that is known to be critical for osseous union.9
Although the literature in orthopaedic surgery is of “low quality”, the evidence for nutritional optimization in the surgical patient is convincing.10 This modifiable risk factor should be optimized before nonunion reconstruction as this poses minimal risk yet the potential for significant benefit. High protein oral nutritional supplements for the “at-risk” surgical patient decreased complications and decreased length of hospital stay in a meta-analysis by Cawood et al11 evaluating 3790 patients from 36 randomized control trials. Similar findings noted in another meta-analysis by Dover et al12 using 35 randomized controlled studies noted the efficacy of presurgical immunonutrition. The rate of infectious complications and hospital length of stay were decreased compared with controls. Thus, there seems to be reasonable evidence that nutritional optimization can lower complications in the orthopaedic surgical patient and increase the likelihood of healing a fracture nonunion.
DOES VITAMIN D IMPACT FRACTURE UNION?
The role of vitamin D in fracture healing has been highly scrutinized in recent years. Basic science studies, suggest that vitamin D has a direct role in the cellular and molecular pathways of fracture healing. Clinical studies have failed to demonstrate its influence on fracture outcomes. Therefore, orthopaedic surgeons have difficulty making data-driven decisions regarding vitamin D testing and supplementation for fracture patients. There are no literature-supported recommendations. This is especially concerning given the high prevalence of hypovitaminosis D in the orthopaedic trauma population.
Vitamin D in humans is either obtained through dietary intake in the form of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) or is minimally produced through light-exposed skin by converting 7-dehydrocholesterol to cholecalciferol. Because it can be synthesized, it is technically a hormone rather than a vitamin. In the liver, the 25-hydroxylase enzyme converts it to calcidiol (25-OH D), and subsequently in the kidney, the 1-hydroxylase enzyme converts calcidiol to calcitriol (1, 25-OH D). Calcidiol is not biologically active and has a 15-day half-life. It is considered the body's vitamin D “reserve” from which biologically active calcitriol can be generated as needed. By contrast, calcitriol has a relatively short half-life of only 15 hours, and its levels can fluctuate more readily than those of calcidiol. For these reasons, serum calcidiol level is considered the best measure of vitamin D status.13,14
Serum calcidiol levels vary greatly throughout the general population and are likely influenced by region and ethnicity. Defining normovitaminosis D is not simple, and the Endocrine Society and the National Academy of Medicine are the 2 organizations that have published the most well-known guidelines based on extensive literature reviews.15,16 (Table 3) The differing guidelines of the 2 organizations have been debated without resolution, which contributes to the uncertainty that we have with thresholds for diagnosing and treating hypovitaminosis D in the orthopaedic trauma population. This controversy and the multiple levels of hypovitaminosis D (deficiency vs. insufficiency) also make it difficult to standardize study designs when investigating vitamin D and fracture healing.
The most well-described effects of vitamin D are increasing intestinal and renal absorption of calcium and phosphate. Both these ions are important for bone formation and remodeling; therefore, vitamin D clearly plays an indirect role in fracture healing.13,16 There is also evidence that vitamin D has a direct role in fracture healing through receptors on osteoblasts, vitamin D metabolites identified in fracture callus, more robust callus formation with supplementation, increased expression of cytokines involved in fracture healing, increased production of proteins including osteocalcin and osteopontin, and increased extracellular matrix mineralization.17–20 Vitamin D also stimulates upregulation of the RANKL pathway in osteoblasts, which leads to increased osteoclastogenesis and may impact fracture remodeling.13,20 However, a true causal relationship or clinically significant effect of vitamin D on fracture healing through these mechanisms remains unproven. Brinker et al4 reported a 68% incidence of hypovitaminosis D in series of 37 patients with no other obvious source of nonunion. Using modern standards of hypovitaminosis D (ie, serum calcidiol <30 ng/mL), the incidence in this series decreases to 57%. Other studies have reported hypovitaminosis D incidences in orthopaedic trauma populations ranging from 62% to 89%.21–25 These findings suggest that the incidence of hypovitaminosis D in the Brinker study population was typical and consistent with a trauma population. Thus, the association between hypovitaminosis D and nonunion may not be substantiated.
Useful data to guide clinical practice are still lacking. Bodendorfer et al26 prospectively followed 201 orthopaedic trauma patients treated with vitamin D supplementation, 83% of which initially had hypovitaminosis D and found no significant association between initial or final vitamin D levels and overall complications or repeat surgery. Gorter et al27 followed 617 orthopaedic trauma patients, of which 249 deficiencies were treated with supplementation. They found significantly more nonunions with uncorrected hypovitaminosis D (3/30) compared with corrected hypovitaminosis D (2/117) and continuous normovitaminosis D (1/382). It is difficult to draw conclusions from this study given the low incidence of nonunion, the short follow-up (4 months), the inclusion of all fracture types, and the lack of clarity concerning the statistical analysis that did not seem to incorporate potential confounding factors. Finally, Haines et al conducted double-blinded randomized placebocontrolled pilot study of 100 patients with long bone fractures randomized to a single high dose of vitamin D supplementation versus placebo. There were 2 nonunions and 7 lost to follow-up in each group after 12-month follow-up.25 The low incidence of nonunion makes it difficult to draw conclusions. The threshold for subject inclusion in this study was serum calcidiol level <30 ng/mL; therefore, it is unknown whether a lower threshold for hypovitaminosis D would have correlated with fracture nonunion.
The lack of evidence to guide clinical practice results in many questions being unanswered. These include the following: (1) What, if any, effect does vitamin D has on fracture healing? (2) What is the correct threshold for hypovitaminosis D? (3) What is the most cost effective strategy for testing or is screening even necessary? (4) Is routine supplementation more cost effective than screening in orthopaedic trauma patients? Until we better understand the relationship between vitamin D deficiency and fracture healing, we will not know when vitamin D supplementation is the difference between union and nonunion.
ARE NONSTEROIDAL ANTI-INFLAMMATORY DRUGS CONTRAINDICATED IN FRACTURE AND NONUNION PATIENTS?
At the molecular level, there are multiple reasons that nonsteroidal anti-inflammatory medications could potentially interfere or inhibit the mechanisms involved in fracture healing. NSAIDs inhibit the enzyme cyclo-oxygenase (COX) that is required in the process whereby arachidonic acid is converted into prostaglandin (PG). PGs have a stimulatory effect on both osteoclast and osteoblast function and are known to be essential in the molecular expression of bone morphogenetic proteins 2 and 7.28 Through the inhibition of COX and the resultant decrease in PG production, new bone formation and fracture healing/repair may be diminished to varying degrees.
The evidence for this effect to translate to decreases in bone healing in animal models and humans is less clear and conflicting. Gerstenfeld et al29 compared placebo, ketorolac (a nonselective COX inhibitor), and parecoxib (a selective COX-2 inhibitor) with respect to COX mRNA production and analysis of callus formation in a rat femur fracture model Compared with placebo, both ketorolac and parecoxib showed decreased mRNA production, callus formation, and strength of callus; however, it was substantially more pronounced with the nonselective COX inhibitor ketorolac. By contrast, another well-done study by Mullis et al30 examined the effects on healing of multiple NSAIDs in a mouse tibia fracture model. These authors found that while ketorolac had a slight decrease in callus density and energy absorption early in the healing phase (4 weeks) when compared with placebo, none of the drugs administered had a detrimental effect on fracture healing, histology, nor mechanical stiffness at any time-point up to 12 weeks.
Clinically, in humans, the data seem to match what we find in the animal model literature. One article in 2010 and 2 in 2014 highlighted the potential of NSAIDs having a real clinical impact on fracture healing in humans. Burd et al31 demonstrated that patients who received indomethacin (nonselective COX inhibitor) for 6 weeks as prophylaxis against heterotopic bone formation after acetabular surgery had a significantly higher risk of developing a nonunion of associated long bone fractures. Patients who had been randomized to receive indomethacin as part of the prophylactic regimen had a 26% rate of nonunion, whereas those who did not (radiotherapy or no prophylaxis) had a 7% rate of nonunion. In corroboration, a 2014 retrospective review by Jeffcoach et al32 reported that the risk of nonunion and infection was twice as high in patients who received NSAIDs postoperatively compared with those who did not. Interestingly, while there were multiple types of NSAIDs administered in this group of patients, all the complications occurred with nonselective ketorolac and ibuprofen. Similarly, Sagi et al33 found that patients who had been randomized to receive 6 weeks of indomethacin for prophylaxis after acetabular repair had more nonunions of the posterior wall (62% nonunion with indomethacin vs. 19% nonunion for placebo). These authors found that short-term treatment with indomethacin for 1 week did NOT increase the rate of nonunion of the posterior wall when compared with placebo. In further support of short-term usage for NSAIDs, Donahue et al found that administration of intravenous ketorolac for acute pain control in the immediate postoperative period (first 48 hours) after fracture repair surgery did not increase the rate of nonunion.34 Finally, in a meta-analysis of 4 articles examining the effect of NSAIDs on long bone fracture nonunion, Dodwell et al35 found 2067 patients received NSAIDs (type and duration NOT specified, all oral route), which resulted in a 7.3% nonunion rate (150 patients), and 9984 patients received opioids only which resulted in a nonunion rate of 1.5%. These results were statistically significant in demonstrating that NSAIDs seemed to have a detrimental effect on fracture healing.
In conclusion, biochemical and animal studies exist that show an inhibitory effect on healing of acute femur and tibia fractures in mice and rats. This negative effect is more pronounced with nonselective COX inhibitors and has been shown to affect, mRNA expression of COX, production of PGs, as well as the histological and biomechanical characteristics of the callous. However, there are other excellent animal studies that refute these findings. Clinical studies in humans show that short-term administration of NSAIDs for immediate postoperative acute pain management do not exhibit this effect on fracture healing, but long-term use of nonselective NSAIDs does seem to increase the risk of nonunion.
As has been highlighted through this article, many factors beyond the surgical variables seem to impact the fracture healing environment in both acute fractures and nonunions. Although not entirely clear, endocrine and nutritional optimization may positively influence fracture healing and warrant further investigation. Vitamin D axis modulation through supplementation is relatively straightforward, but its impact has not reliably demonstrated a positive impact on fracture/nonunion healing. Finally, reasonable human clinical data implicates longer-term use of NSAIDs with inhibited fracture healing and nonunion, but short-term use does not have the same detrimental effect. At present, the fracture surgeon must consider each individual patient and weigh the benefits versus the costs of host optimization.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
fracture healing; nonunion; nutritional optimization; endocrine abnormalities; NSAIDs