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Evidence-Based Systematic Review

Nonsteroidal Anti-Inflammatory Drugs and Bone-Healing

A Systematic Review of Research Quality

Marquez-Lara, Alejandro MD1,b; Hutchinson, Ian D. MD1; Nuñez, Fiesky Jr. MD, PhD1; Smith, Thomas L. PhD1; Miller, Anna N. MD1,a

Author Information
doi: 10.2106/JBJS.RVW.O.00055
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  • Disclosures

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been utilized to treat pain, fever, and inflammation since the nineteenth century and are among the most commonly utilized medications in the world today1. With few exceptions, NSAIDs have become the safest and most effective drugs to treat postoperative pain2,3. Despite these benefits, NSAIDs are thought to cause delayed bone-healing and nonunions and are often withheld following orthopaedic procedures4-11. Other studies have shown that NSAIDs are safe following fracture fixation and spinal fusions without considerable effects on bone-healing12-15. These discrepancies in the literature have been the subject of debate in numerous literature reviews16-39, instructional course lectures40,41, best-evidence topic reports42, commentaries43-48, expert opinions49, editorials50,51, and even lay-press articles52,53.

It is widely accepted that the existing literature has substantial methodological limitations; however, the actual quality of the literature and the factors that influence its divergent interpretation have not previously been characterized, to our knowledge. The goals of this systematic review are fourfold: (1) to offer a comprehensive assessment of the basic-science, pre-clinical, and clinical literature evaluating the effects of NSAIDs on bone-healing; (2) to characterize the methodological quality in the published literature addressing the effects of NSAIDs on bone-healing; (3) to identify elements in study designs that contribute to conflicting interpretations of results and recommendations in the published literature; and (4) to suggest methodological characteristics that may help future studies to better characterize the impact of NSAIDs on bone-healing.

Materials and Methods

A literature search was performed through the MEDLINE and Embase databases utilizing the following free-text and MeSH terms: nonsteroidal anti-inflammatory agents, NSAID, fracture-healing, bone healing, spinal fusion, and cyclooxygenase-2 inhibitors. All articles addressing the impact of NSAIDs on bone-healing and fracture-healing following orthopaedic procedures were identified. Specifically, we included studies that assessed either fracture-healing or spinal fusion, but we excluded those that assessed the impact of NSAIDs on bone metabolism, bone mineral density, fracture risk, heterotopic ossification, and osseous ingrowth onto metal implants. Non-English-language manuscripts, in vitro and animal studies, case reports, studies not specifically associated with bone-healing, and those performed on a pediatric population were also excluded. Literature reviews that cited pediatric studies were still included for analysis as a potential factor that may have influenced the authors’ conclusions and recommendations. All prospective and retrospective human studies and literature reviews were identified for further evaluation. References of all selected articles were reviewed to ensure that all relevant studies would be included for analysis. A total of twelve clinical articles and twenty-four literature reviews were selected (Fig. 1). The literature search was conducted on two separate occasions (January 5, 2015, and March 2, 2015) independently by two of the authors (A.M.-L. and I.D.H.) following recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines54. Records were stored in a computer-based referenced management system (EndNote, Thomson Reuters).

Fig. 1
Fig. 1:
Flowchart of the structured database search that formed the basis of the literature review.

Clinical studies were reviewed to specifically assess the type of NSAID utilized, dose, route of administration, length of NSAID administration, type of bone fixation, effect on bone-healing, and critical methodological limitations. A modified Coleman Methodology Score was utilized to assess the methodology of the clinical studies. The Coleman Methodology Score is based on a subsection of the Consolidated Standards of Reporting Trials (CONSORT) statement55,56, and has been validated and has been utilized by several published reports in the orthopaedic literature57-59. The Coleman Methodology Score utilizes ten criteria, giving a total score between 0 and 100 points56. A methodological score of 100 points indicates that the study is methodologically sound and largely avoids chance, various biases, and confounding factors. For the purpose of this review, the terms surgical description, postoperative rehabilitation, and diagnostic certainty were substituted for description of NSAID regimen and monitoring of postoperative NSAID utilization, and scores were adjusted accordingly to add up to 100 points. Previous studies have modified the original Coleman Methodology Score to accommodate for specific topics and study objectives57,59. The categorical rating was considered to be excellent if the score was 85 to 100 points, good if it was 70 to 84 points, fair if it was 55 to 69 points, and poor if it was ≤54 points59.

Both the clinical and review articles were analyzed with regard to country of origin, impact factor, author specialty and profession, and final interpretation and recommendation. Reviews were assessed for the quality and quantity of cited clinical studies. In addition, a twenty-seven-item checklist (www.prisma-statement.org/) was utilized to assess the quality of any systematic review or meta-analysis. Clinical studies were further analyzed with regard to the reported nonunion rates, functional outcomes (when available), and post hoc power calculations.

Statistical Analysis

Statistical analysis was performed with use of SPSS version 20 (IBM). All data were checked for normal distribution (the Kolmogorov-Smirnov test, the Shapiro-Wilk test, and the Pearson skewness coefficient). The chi-square test was utilized for categorical data, and either the Student t test or the analysis of variance (ANOVA) with post hoc pairwise analysis (Bonferroni) was utilized for continuous data. A p value of <0.05 was utilized to denote significance. Pearson correlation analysis, with a 95% confidence interval (95% CI), was utilized to correlate the modified Coleman Methodology Score with the number of times that each study was cited, the journal impact factor, and the year of publication to investigate trends in methodology over time. Lastly, all post hoc power calculations were performed with use of G*Power software (University of Dusseldorf).

Results

Clinical Studies

A complete list of the twelve clinical studies included in this analysis along with study characteristics and modified Coleman Methodology Score can be found in Table I. Based on the modified Coleman Methodology Score, none were excellent, one was good (a Coleman Methodology Score of 70 points), three were fair (a Coleman Methodology Score of 56 to 66 points), and eight were poor (a Coleman Methodology Score of 20 to 54 points). Only three of the studies were randomized controlled trials, and the other nine studies were retrospective chart reviews. Nonunion rates varied widely between studies (0% to 65.6% in the NSAID groups and 0% to 19.0% in the control groups), and only four studies showed any sort of functional outcomes. Based on the power calculations, only five of the twelve clinical studies had a power of >80%.

TABLE I - Clinical Studies That Analyzed the Impact of NSAIDs on Bone-Healing*
Study Impact Factor (2015) Design Study Power§ No. of Patients Patient Age# Bone Type and Treatment NSAID (COX-2/COX-1 Ratio)** Time to First Dose After Injury or Procedure Length of Administration Dose Nonunion or Delayed Union Rates Functional Outcomes Effect on Bone-Healing Follow-up Coleman Score Times Cited by Reviews
Davis and Ackroyd12 (1988) 0.238 RCT 66.7 98 55.7-64.1 Colles fracture, nonoperative Flurbiprofen (24) <24 hr 14 d 50 mg every 4-8 hr 0% for both NSAID and control Grip strength None 1 yr 66 5
Park et al.4 (2005) 1.263 Retro 52.0 88 52-54 (20-67) Spine (varied pathology), PL fusion Ketorolac (1176) <24 hr 3 d 120 mg continuous (PCA) NSAID: 16.7%, control: 3.4% Kim and Kim clinical outcomes Negative 1 yr 43 4
Adolphson et al.13 (1993) 1.31 RCT 33.8 42 63 (52-79) Displaced Colles fracture, nonoperative Piroxicam (2.1) <48 hr 56 d 20 mg every 24 hr NR Grip strength and ROM None 3 mo 62 10
Sagi et al.10 (2014) 1.54 RCT 69.6 98 34-46 (18-67) Acetabular fracture, ORIF Indomethacin (11) <24 hr 3 d, 1 wk, 6 wk 75 mg every 24 hr NSAID: 62.0%, control:19.0% ROM Negative (only with 6 wk) 6 mo 70 0
Deguchi et al.7 (1998) 1.888 Retro 62.6 73 38 (19-66) Spine (isthmic spondylolisthesis), PL fusion NS NS >60 d NS NSAID: 65.6%, control: 2.2% Return to work Negative 1-7 yr 56 8
Glassman et al.8 (1998) 2.447 Retro 94.8 288 43-45 Spine (varied pathology), PL fusion Ketorolac (1176) <24 hr Variable (in-hospital only) 30 mg every 8 hr NSAID: 17.0%, control: 4.0% NR Negative 2 yr 50 22
Pradhan et al.14 (2008) 2.447 Retro 99.9 405 56.0-56.3 Spine (varied pathology), PL fusion Ketorolac (1176) <24 hr 48 hr 30 mg every 6 hr NSAID: 5.3%, control: 6.2% NR None 1 yr 47 5
Jeffcoach et al.9 (2014) 2.495 Retro 99.1 1901 43.6-47.0 Trauma (long-bone fractures), NS Ketorolac (1176), ibuprofen (1.2), meloxicam (0.32), celecoxib (0.21), diclofenac (0.27), naproxen (2.4), indomethacin (11), nabumetone (4.5) 24-48 hr Variable (in-hospital) Ketorolac (15-30 mg), ibuprofen (600 mg), meloxicam (8-15 mg), celecoxib (150-200 mg), diclofenac (0.023-25 mg), naproxen (500 mg), indomethacin (75 mg), nabumetone (750 mg) NSAID: 3.0%, control: NR NR Negative NS 20 0
Burd et al.5 (2003) 2.735 Retro 81.9 112 38.1-39.5 Acetabular fracture, NS Indomethacin (11) <24 hr 42 d 25 mg every 8 hr NSAID: 26.0%, control: 7.0% NR Negative 3-12 mo 27 14
Giannoudis et al.6 (2000) 2.735 Retro 84.7 99 35-38 (18-85) Femoral shaft, IM nail Ibuprofen (1.2), diclofenac (0.27) NS 7-154 d NS NR NR Negative†† 6-18 mo 30 15
Lumawig et al.11 (2009) 2.8 Retro 99.6 273 60 (21-90) Spine (varied), PL fusion Diclofenac (0.27) <24 hr 14 d 75-150 mg every 24 hr High dose: 33.7%, low dose: 9.5%, control: 0% NR Negative‡‡ 2 yr 54 4
Bhattacharyya et al.15 (2005) 7.871 Retro 99.9 9995 77-78 Humeral shaft, nonoperative NS Variable 0-30, 31-60, 61-90 d NS NSAID: 3.1%, control: 0.8% NR None 3 mo 49 8
*RCT = randomized controlled trial, NR = not reported, NS = not specified, ORIF = open reduction and internal fixation, ROM = range of motion, retro = retrospective, IM = intramedullary, PL = posterolateral, and PCA = patient-controlled analgesia.
The specialty for all of these authors was orthopaedic, except for Jeffcoach et al., who had a general surgery specialty.
All prospective randomized controlled trials were blinded.
§Study power calculations were based on each study’s hypothesis, sample size, effect size, statistical analysis, and alpha level.
#The values are given as the range or as the mean with the range in parentheses.
**COX-2/COX-1 ratios are based on the 80% inhibitory concentration (IC80) from human whole-blood assays. The higher the number, the less COX-2 selectivity (compare celecoxib [0.21] with ketorolac [1176]). The values in this column were obtained from: Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sc U S A 1999;96:7563-8.
††The normal healing group reported NSAID use for a mean time of seven days.
‡‡Nonunions were observed only in the high-dose group (>300 mg) within two weeks, and 9.5% of patients in the low-dose group (25 to 300 mg) experienced delayed union (more than twelve months until radiographic fusion).

Overall, the research quality was poor, with a mean modified Coleman Methodology Score (and standard deviation) of 47.8 ± 14.5 points (range, 20 to 70 points). There were notably low mean scores in the type of study design (3.75 ± 6.50 points), in the postoperative NSAID monitoring (4.17 ± 4.93 points), in the procedure for assessing outcomes (2.85 ± 2.33 points), and in the description of the subject selection process (4.83 ± 2.11 points) (Table II).

TABLE II - Mean Modified Coleman Methodology Score per Section for All Clinical Studies
Possible Score (Points) Modified Coleman Methodology Score*
Part A
 Study size 0 to 10 6.42 ± 3.35 (0 to 10)
  Fewer than fifty patients 0
  Fifty to 100 patients 4
  101 to 200 patients 7
  More than 200 patients 10
 Mean follow-up duration 0 to 5 2.25 ± 1.79 (0 to 5)
  Less than six months (or not stated or unclear) 0
  Six to twelve months 2
  More than twelve months 5
 No. of different procedures included for each reported outcome 0 to 10 8.33 ± 3.73 (0 to 10)
  <90% 0
  ≥90% 7
  Only one procedure 10
 Type of study 0 to 15 3.75 ± 6.50 (0 to 15)
  Retrospective 0
  Cohort 10
  Randomized controlled trial 15
 Description of NSAID utilization 0 to 10 7.50 ± 3.82 (0 to 10)
  No information 0
  Partial information or multiple NSAIDs 5
  Type, dose and rate, route, length 10
 Postoperative NSAID monitoring 0 to 10 4.17 ± 4.93 (0 to 10)
  No or not mentioned 0
  Yes 10
Part B
 Outcome criteria 0 to 10 8.00 ± 3.56 (0 to 10)
  Clearly defined 2
  Timing of outcome assessment clear 2
  Use of outcome criteria has good reliability 3
  Use of outcome with good sensitivity 3
 Procedure for assessing outcomes 0 to 15 2.85 ± 2.33 (0 to 7)
  Subjects recruited 5
  Investigator independent of surgeon 4
  Written assessment 3
  Completion of assessment by subjects themselves with minimal investigator assistance 3
 Description of subject selection process 0 to 15 4.83 ± 2.11 (0 to 10)
  Selection criteria reported and unbiased 5
  Recruitment rate reported
   ≥80% 5
   <80% 3
  Eligible subjects not included in the study satisfactorily accounted for or 100% recruitment 5
Maximum score 100 47.80 ± 14.50 (20 to 70)
*The values are given as the mean and the standard deviation, in points, with the range in parentheses.

Based on the study conclusions and recommendations, the mean modified Coleman Methodology Score was significantly lower (p = 0.032) in clinical studies that demonstrated a negative effect of NSAIDs on bone-healing (40.0 ± 14.3 points) compared with the studies that showed a neutral effect (58.8 ± 10.3 points) (Table III). On average, the journal impact factor, author specialty (percentage of orthopaedic surgeons), country of origin (United States compared with outside the United States), year of publication, or number of times cited by reviews did not significantly differ (p > 0.05) between studies with contrasting views on the effects of NSAIDs on bone-healing. The three studies most often cited by literature reviews (fourteen to twenty-two times) were all studies that concluded that NSAIDs had a detrimental effect on bone-healing. In contrast, none of the clinical studies that concluded that NSAID use was appropriate were cited more than ten times by the reviews.

TABLE III - Characteristics of Studies with Divergent Recommendations with Regard to the Utilization of NSAIDs
Recommendation
Characteristics Avoid NSAIDs NSAIDs Are Safe P Value
No. of studies 7 5
Modified Coleman score*(points) 40.0 ± 14.3 58.8 ± 10.3 0.032
No. of patients* 404.9 ± 665.7 2127.6 ± 4400.3 0.323
Journal impact factor* 2.3 ± 0.6 2.7 ± 3.0 0.343
No. of times cited by reviews* 9.6 ± 7.7 5.6 ± 3.8 0.318
United States as country of origin 57.1% 60.0% 0.921
Orthopaedics as author specialty 85.7% 100.0% 0.897
Year of publication 0.634
 1980 to 1999 28.6% 40.0%
 2000 to 2004 28.6% 0%
 2005 to 2009 28.6% 40.0%
 2010 to 2014 14.3% 20.0%
Spine as anatomical region 57.1% 20.0% 0.293
*The values are given as the mean and the standard deviation.
Other anatomical regions included the distal part of the radius, the midshaft of the femur, the midshaft of the humerus, and the acetabulum.

Correlation analysis demonstrated that there was no significant relationship between the modified Coleman Methodology Score and the year of publication (r = −0.313, p = 0.321) or journal impact factor (r = −0.247, p = 0.440). Similarly, there was no correlation between the journal impact factor and the number of times that a study was cited (r = 0.137, p = 0.670).

Review Articles

A complete list of the twenty-four literature reviews included in this analysis along with study characteristics and the summaries of the authors’ conclusions and recommendations can be found in Table IV. There were two meta-analyses, and twenty-two narrative reviews. Unanimously, all review articles described important limitations in the available literature and discussed the need for prospective randomized controlled trials to help clarify the effects of NSAIDs on bone-healing. The four literature reviews that included studies on pediatric populations all concluded that either short-term NSAID use was safe or there was no clear contraindication to NSAID utilization during bone-healing27-29,33.

TABLE IV - Literature Reviews That Analyzed the Impact of NSAIDs on Bone-Healing
Study Design Author Specialty* Country of Origin Journal Impact Factor No. of Clinical Studies Cited Summary of Recommendations Based on Conclusions from Literature Review
Dumont et al.16 (2000) Narrative review Neurosurgery Canada 2.15 1 Benefit does not outweigh risks
Harder and An17 (2003) Narrative review Orthopaedics U.S. 2.472 7 No clear recommendations
Bandolier Extra18 (2004) Narrative review PhD Europe NA 4 No clear recommendations
Thaller et al.19 (2005) Narrative review Orthopaedics U.S. 0.977 1 Avoid NSAIDs; treat as similar to tobacco use
Radi and Khan20 (2003) Narrative review DVM U.S. 2.143 4 No clear recommendations
Vuolteenaho et al.21 (2008) Narrative review Rheumatology Europe 2.294 6 Alternative pain treatment modalities should be sought where impaired bone-healing is a problem
Gaston and Simpson22 (2007) Narrative review Orthopaedics Europe 2.735 2 Avoid during fracture repair
Pountos et al.23 (2008) Narrative review Orthopaedics Europe 2.462 6 No clear recommendations
Boursinos et al.24 (2009) Narrative review Orthopaedics Europe 2.4 2 COX-2 inhibitors are preferred and for short duration; should avoid in cases with high risk of nonunion
Xian and Zhou25 (2009) Narrative review PhD Australia 10.252 0 No clear recommendations
Barry26 (2010) Narrative review DVM U.S. 1.031 8 No clear recommendations
Dodwell et al.27§ (2010) Meta-analysis Orthopaedics U.S. 2.748 10# No clear contraindication, but care should be taken in patient selection
Li et al.28§ (2011) Meta-analysis Orthopaedics China 2.447 7# NSAID effect is dose-dependent; short-term exposure to normal dose is likely safe
Pountos et al.29 (2012) Narrative review Orthopaedics Europe 1.524 13# Consider NSAIDs for low-risk patients and for a short period, probably not exceeding a week after fracture
Kurmis et al.30 (2012) Narrative review Orthopaedics Australia 3.243 3 No evidence to deny patients with simple fracture their analgesic benefits, but should be avoided in high-risk patients
van Esch et al.31 (2013) Narrative review PhD Europe 1.152 0 Restricted use
Su and O’Connor32 (2013) Narrative review MS U.S. 3.434 2 No clear recommendations (authors point to potential drawbacks of NSAIDs)
Geusens et al.33 (2013) Narrative review Rheumatology Europe 5.073 13# Short-term duration is safe, but should be avoided in high-risk patients
Abdul-Hadi et al.34 (2009) Instructional course lecture Orthopaedics U.S. 4.309 6 No clear recommendations
Cottrell and O’Connor35 (2010) Narrative review PhD U.S. NA 6 No clear recommendations, but clearly point to the potential drawback of NSAIDs
Ziltener et al.36 (2010) Narrative review PM&R Europe 0.787 0 Avoid during fracture repair
Wheeler and Batt37 (2005) Narrative review Sports medicine Europe 4.171 4 Avoid during fracture repair
Dahners and Mullis (2004)39 Narrative review Orthopaedics U.S. 2.403 3 Avoid when healing is desired
Gajraj (2003)38 Narrative review Anesthesia U.S. 2.12 3 No clear recommendations
*PhD = Doctor of Philosophy, DVM = Doctor of Veterinary Medicine, MS = Master of Science, and PM&R = physical medicine and rehabilitation.
Europe includes Spain, the Netherlands, United Kingdom, Finland, Switzerland, and Italy.
NA = not available.
§In the PRISMA checklist results of twenty-seven items, Dodwell et al. completed twenty-seven items and Li et al. completed twenty-six items.
#These numbers include studies from pediatric populations in the review.

The mean number of clinical studies (and standard deviation) cited in review articles that concluded that NSAIDs were safe to use (8.0 ± 4.8) was significantly greater (p = 0.008) compared with those that recommended avoiding NSAIDs (2.1 ± 2.1) (Table V and Fig. 2). Similarly, the quality of clinical studies was higher among the studies that concluded that NSAID utilization was safe (50.9 ± 11.1) compared with those that recommended against NSAID utilization (32.7 ± 21.3) or that had no clear recommendations (39.8 ± 15.3); however, this was not significant (p = 0.156). Journal impact factor, author specialty (percentage of orthopaedic surgeons), country of origin (United States compared with outside the United States), and year of publication did not vary significantly (p > 0.05) when comparing reviews of various conclusions and recommendations. The two meta-analyses were performed in accordance with the PRISMA guidelines.

TABLE V - Characteristics of Reviews with Conflicting Recommendations with Regard to the Utilization of NSAIDs
Recommendations
Characteristics Avoid NSAIDs NSAIDs Are Safe No Clear Recommendations P Value
No. of studies 8 6 10
No. of clinical studies cited* 2.1 ± 2.1 8.0 ± 4.8 4.0 ± 2.5 0.008
Coleman score of clinical studies cited*(points) 32.7 ± 21.3 50.9 ± 11.1 39.8 ± 15.3 0.156
Total no. of patients from clinical studies cited* 1549.6 ± 3665.6 8033.2 ± 5490.5 3510.8 ± 5025.3 0.057
Orthopaedics as author specialty 37.5% 83.3% 30% 0.099
Journal impact factor* 2.08 ± 1.12 2.91 ± 1.20 3.53 ± 2.88 0.361
United States as country of origin 25% 16.7% 70% 0.056
Year of publication 0.092
 2000 to 2004 37.5% 0% 30%
 2005 to 2009 50% 16.7% 40%
 2010 to 2014 12.5% 83.3% 30%
*The values are given as the mean and the standard deviation.
A post hoc test (Bonferroni) identified a significant difference between reviews that concluded that NSAIDs were safe to use compared with those that concluded that NSAID use should be avoided (p = 0.007).

Fig. 2
Fig. 2:
Number of times each review cited a clinical study (y axis), stratified by authors’ recommendations (x axis). Review articles are identified by the name of the first author. Gray bars represent adult studies and black bars represent pediatric studies.

Several reviews cited identical clinical studies but showed conflicting conclusions and recommendations (data not shown). The two reviews with the highest number of clinical citations (n = 10) agreed that NSAID administration was safe as long as the duration was short (one week)29,33. Of note, both studies pointed out that NSAIDs should be avoided in patients at risk for delayed healing or if the fracture shows signs of delayed union or nonunion.

Discussion

Postoperative pain control, particularly in orthopaedic patients, continues to be a challenge60,61. The use of multimodal analgesia, in which NSAIDs play an important role, has helped to make great strides in improving acute pain management and has been utilized extensively in patients undergoing total joint arthroplasty62-65. Although there is some evidence that this practice is being adopted by other orthopaedic specialties, fracture repair surgeons would often prefer not to use NSAIDs, thereby avoiding any risk of impaired healing37. However, this has led to an increase in the use of opiates, along with their many drawbacks, during the postoperative period66.

NSAIDs are known to inhibit both cyclooxygenase (COX) enzyme isoforms (COX-1 and COX-2), with varying degrees of selectivity depending on the type of NSAID. This inhibition decreases prostaglandin levels, which play a major regulatory role in all stages of the bone-healing cascade, particularly the early inflammatory phase67-69. Thus, it is reasonable to predict that NSAID administration may affect bone-healing. However, as demonstrated by this review, results from the published literature are highly variable and demonstrate methodological limitations.

Considerations from Basic-Science Studies

It is clear from the basic-science literature that studying the effects of NSAIDs on bone-healing is extremely challenging. Based on the physiological requirements of the bone, prostaglandins either can promote bone resorption by directly increasing osteoclast activity or can stimulate bone production by activating osteoblast differentiation70-73. Prostaglandins exert this range of action through a variety of G-protein-coupled receptor subtypes (EP1 to EP4). Although activation of EP2 and EP4 receptors promotes bone-healing, EP1-receptor activation has been shown to have a major inhibitory effect on bone-healing74-77. The effect of NSAIDs on the expression of these receptors has not been fully elucidated, but may help to explain some of the discrepancies between basic-science and clinical studies.

Animal studies have helped to advance our understanding of the physiological events critical to normal bone-healing78,79. This has led to the development of novel gene-therapy models (e.g., COX-2 transgene) that have shown to increase recruitment and expansion of mesenchymal stem cells, decrease cartilaginous callus formation, and increase angiogenesis-dependent cartilage remodeling within the healing fracture callus80,81. However, extrapolating the impact of NSAIDs in animal models to humans should be done with caution. The type of NSAID and its bioavailability are known to be highly variable between animal species and may not be taken into consideration in experimental designs47,82. Furthermore, there is great variability in the timing and length of exposure, which also appears to influence the impact of NSAIDs on bone-healing83,84. Although continuous and prolonged exposure to NSAIDs (greater than six weeks) may inhibit or may at least delay bone-healing in animals85-90, in a clinical setting, patients are more likely to receive short-term exposure (three to twenty-one days)4,8-12,14, and any detrimental effect to bone-healing would likely be reversible after discontinuation of the NSAID91. Furthermore, existing animal models fail to consider the major inflammatory insult associated with surgical fixation92,93.

In vitro and in vivo animal studies have helped to advance our understanding of the physiological events critical to normal bone-healing. In addition, they have provided insight into the effects of both COX-2-specific and non-specific NSAIDs on bone-healing35. However, the great variability in study design and the inherent limitations of basic-science models have led to inconsistent and variable effects of NSAIDs on bone-healing and have failed to translate into clinical practice.

Clinical Studies: Limited Quality of Evidence

From a methodological perspective, trying to understand the impact of NSAIDs on bone-healing in a clinical setting is extremely challenging. It is widely accepted that numerous confounding factors (e.g., smoking, diabetes, obesity) affect bone-healing, and controlling for these in a prospective study requires considerable time and planning94. These difficulties may help to explain the limited quality of clinical studies included in this review. Eight of the twelve studies received a modified Coleman Methodology Score of <54 points and were classified as being of poor quality. Factors that contributed to the low methodological scores were the type of study design, postoperative NSAID monitoring, procedure for assessing outcomes, and description of subject selection process. With the exception of postoperative NSAID monitoring, which was unique to this review, the areas of methodological deficiency identified in this analysis have been reported in the published literature as common weaknesses in orthopaedic trials56,58,59. Unfortunately, there was no correlation between modified Coleman Methodology Score and year of publication, which suggests that the quality of research in this area has not improved in the past decades.

The three clinical trials with the highest modified Coleman Methodology Score (62 to 70 points) were all prospective randomized controlled trials that showed no negative effect of NSAIDs on bone-healing10,12,13. Of these, only the study by Sagi et al. showed a greater risk of nonunion after six weeks of indomethacin exposure10, which supports the findings of Burd et al., whose 2003 article has been highly cited5. However, it is important to note that even in the former study, one week of indomethacin exposure was not associated with an increased risk of nonunion10. Ketorolac was also associated with delayed bone-healing in two studies after more than forty-eight hours of exposure4,8, although other studies have shown that exposure for less than forty-eight hours did not have any detrimental effects on bone-healing compared with controls14. Similar observations with regard to timing and dose have been noted elsewhere11,15. In one study, NSAID utilization was associated with a higher rate of nonunions; however, this was only true for patients who took NSAIDs on days 61 to 90 after surgery15. As others have mentioned, this was likely related to the pain associated with the nonunion, demonstrating an association, not proving causation21. Another study demonstrated a positive correlation between time to union and the amount of diclofenac used (r = 0.271; p < 0.001). Although high-dose diclofenac (>300 mg for two weeks) was associated with nonunions, normal dosing did not have a major effect11. These observations highlight the importance of monitoring the type, dose, timing, and duration of NSAID exposure to better understand how these drugs may be safely utilized in the setting of bone-healing. Unfortunately, only five of the twelve clinical studies in the current study showed some sort of long-term NSAID monitoring7,10,12,13,15.

Despite many efforts, the quality of evidence with regard to the effects of NSAIDs on bone-healing is limited, particularly in the adult literature. Although most authors have stated that a large, multicenter, randomized controlled trial is warranted, few have provided specific details of a proposed research design. Future studies should aim for a well-designed prospective trial, with clearly defined end points as suggested by Jakobsen et al.57, as well as strict NSAID-administration parameters (Table VI). At this point, to our knowledge, there have been no excellent studies in the published literature addressing the effects of NSAIDs on bone-healing; therefore, it is difficult to assess the amount of high-quality studies that would be needed to accurately determine the effects of NSAIDs on bone-healing.

TABLE VI - Recommendations for Future Study Designs to Address the Impact of NSAIDs on Bone-Healing*
Study design: A double-blinded randomized controlled trial with a clearly defined hypothesis and one clearly defined primary end point (i.e., radiographic nonunion at six months or time to radiographic union)
 Multicenter
 Three groups: no NSAIDs, non-selective NSAIDs, and COX-2 inhibitors
 Power analysis for the primary end point should be calculated prior to any data collection to determine sample size; an example of primary outcome is radiographic nonunion at six months for three groups analyzed by chi-square and post hoc odds ratio, assuming an alpha set at 0.05, power set at 95%, and a small effect size (a sample size of n = 1545)
 Secondary end points should only be used as supportive evidence to the primary hypothesis (i.e., pain scores and functional outcomes)
 Patient inclusion and exclusion criteria (including comorbidities) should be clearly established and reported
 The recruitment rate should be reported, and attempts should be made to account for eligible patients who are not included and those who are lost to follow-up
 Criterion of a predetermined early stopping rule
 An interim analysis timeline should be followed with clear stopping criteria
NSAID data
 Type (COX selectivity)
 Dose
 Timing of first dose
 Route of administration (oral compared with intravenous)
 Frequency
 Duration
 Detailed NSAID-monitoring protocols should be established and reported, attempts should be made to monitor compliance, and the protocols should be applied in a standardized manner to both patient cohorts
Outcomes
 Assessments should be both clinical and functional and made by an independent investigator
 Validated outcome measurements for use on patients with abnormal bone-healing
 The assessment should be in a written form and ideally be completed by the patient without investigator assistance
 The timing of the outcome assessment should be clearly stated
 The minimum duration of follow-up should be more than twelve months
Things to avoid
 Multiple types of NSAIDs
 Multiple fracture types
 Multiple indications for spinal fusions
 Results from various time points after surgery should not be reported as one outcome
*Some of the recommendations were adapted from the study by Jakobsen et al., who found similar weaknesses in the literature with regard to cartilage repair57. Slight modifications were made specific to NSAID utilization and bone-healing.
Sample size will vary on the basis of the primary outcome, statistical analysis, and number of groups.

Literature Reviews: Variability in Conclusions and Recommendations

The vast majority of reviews (twenty-two [91.7%] of twenty-four) in this analysis were narrative reviews. Narrative reviews offer a comprehensive, generally up-to-date summary of the available literature and provide a broad perspective on a given topic. However, in this type of review, authors have the risk of selecting research that helps to present their argument, which can result in contradictory conclusions and recommendations95. These types of discrepancies have previously been described by Geusens et al., who noted that many review articles and editorials reached different conclusions and provided conflicting recommendations despite citing the same clinical studies33. However, the present study highlights that the majority of review articles were not referencing the same literature and that the quality and quantity of clinical studies included in a literature review substantially impacted the overall message.

The only two meta-analyses in this review offered interesting perspectives on both the quality of the literature and the NSAID effects on bone-healing. In one meta-analysis, we noted an association between low-quality and moderate-quality studies and an increased reported risk of nonunions27. The lower-quality studies were long-bone fracture studies, and higher-quality studies originated from the spine literature. When data from the higher-quality spine studies were pooled into their analysis, there was no increase in the risk of nonunion with NSAID exposure. Our results agree with an association between higher-quality studies and no evidence of negative effects of NSAIDs on bone-healing; however, we were unable to find a significant association (p < 0.05) with the anatomic region. In our study, four (57.1%) of the seven clinical studies that recommended avoiding NSAID exposure were from the spine literature, compared with one (20%) of the five studies that concluded that NSAID use was acceptable; however, this difference was not significant (p = 0.293) (Table III). Furthermore, the mean modified Coleman Methodology Score was not significantly different (p = 0.705) between spine studies (50.5 ± 5.2 points) and fracture studies (46.3 ± 20.5 points). The fact that we excluded pediatric studies from our analysis might explain these differences, as two of the spine studies96,97 reviewed by Dodwell et al.27 were performed in pediatric populations. In contrast to the adult literature, in the pediatric orthopaedic literature there appears to be consensus that NSAIDs do not affect bone-healing96-100.

In the other meta-analysis28, the authors only included spinal fusion studies on adult patients and concluded that short exposure (less than fourteen days) to a normal dose of NSAIDs did not increase the risk of nonunion, which could represent a potential regimen for NSAID administration. Although the authors highlighted clear limitations in the available literature, they failed to exclude a retracted study by Reuben et al.101. This information should be taken into consideration when interpreting their results. Despite these limitations, both meta-analyses were in accordance with the PRISMA guidelines for conducting quantitative systematic reviews and, in our opinion, contributed to the quality of evidence related to NSAIDs and bone-healing. None of the reviews published after these reports (van Esch et al.31, Su and O’Connor32, Geusens et al.33, Kurmis et al.30, and Pountos et al.29) referenced the meta-analysis by Li et al.28, and only one (Geusens et al.33) referenced the meta-analysis by Dodwell et al.27.

Limitations

There were several limitations to our study that must not be overlooked. Studies that did not mention the specific NSAID type, dose, and route of administration were included for the purpose of this review to help to assess elements that may affect the interpretation of the effects of NSAIDs on bone-healing. Studies missing these parameters received low modified Coleman Methodology Scores, which may have reduced the overall scores. However, these parameters were intentionally added to highlight the importance of including this information in clinical studies. In addition, two different reviewers scored each study independently, and any discrepancies were discussed with the senior author until a consensus was reached. We believe that these strict grading parameters enhanced the quality of our review and offered insight into improving future clinical studies. We did not offer insight on the fracture risk, if any, of chronic NSAID administration. However, studies that have assessed this particular point have demonstrated no increased fracture risk with either chronic or occasional use of NSAIDs102,103. We excluded studies in pediatric populations as the majority have demonstrated no detrimental effects on bone-healing96-100. It is widely accepted that pediatric patients should not be compared with adults, particularly with regard to orthopaedic problems104. However, literature reviews that cited pediatric studies were still included to highlight factors that may have affected the authors’ conclusion and recommendations. We also excluded studies examining osseous ingrowth and heterotopic ossification105-107. Although there may be overlap between these two phenomena and fracture-healing, the mechanism is not completely understood. Several studies addressing the effects of NSAIDs on spinal fusion101,108 were not included in this analysis because of fraud allegations that question the veracity of those results. In those studies, COX-2 inhibitors, particularly celecoxib, were found not to impact normal bone-healing108. It is important to note that all of the studies included in this systematic review assess non-selective NSAIDs, and, to date, to our knowledge, there have been no published reports on selective COX-2 inhibitors. Lastly, this review did not provide any pooled analysis between study populations to determine the impact of NSAIDs on bone-healing, based on the type of NSAID, nonunion rates, and functional outcomes. Although this information is critical for the clinical application of these medications, the purpose of this study was instead to offer the reader an opportunity to reflect on the quality of research that is guiding orthopaedic practice. In the age in which evidence-based medicine represents the foundation to the standard of care, the current evidence does not allow orthopaedic surgeons to accurately recommend for or against the use of NSAIDs.

Conclusions

Much effort has been invested in both basic-science and clinical studies to better understand the effect of NSAIDs on bone-healing. Nonetheless, the literature still does not offer a clear consensus with regard to the safety or harm of NSAID utilization following orthopaedic procedures. The great variability in the interpretation of the available evidence appears to suggest that NSAIDs may affect bone-healing, but that this effect depends on the type, dose, timing, and length of exposure. However, the purpose of this study was not to offer a definitive conclusion on the effects of NSAIDs on bone-healing, but to highlight the factors in the literature that may impact the interpretation of these results. It is important for future studies to aim for the most appropriate methodological design, but it is the responsibility of those who read the literature to be critical and, at times, skeptical of both clinical studies and literature reviews that may affect the quality of care for orthopaedic patients109.

Source of Funding:This study was planned and executed without any external funding source.

Investigation performed at the Department of Orthopaedic Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Also, one or more of the authors has had another relationship, or has engaged in another activity, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

References

1. Rainsford KD. Anti-inflammatory drugs in the 21st century. Subcell Biochem. 2007;42:3-27.
2. Bandolier Extra. Acute pain. 2003 Feb. http://www.medicine.ox.ac.uk/bandolier/Extraforbando/APain.pdf. Accessed 2015 Aug 5.
3. Ong CK, Lirk P, Tan CH, Seymour RA. An evidence-based update on nonsteroidal anti-inflammatory drugs. Clin Med Res. 2007 Mar;5(1):19-34.
4. 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 Apr 30;46(2):245-51.
5. Burd TA, Hughes MS, Anglen JO. Heterotopic ossification prophylaxis with indomethacin increases the risk of long-bone nonunion. J Bone Joint Surg Br. 2003 Jul;85(5):700-5.
6. 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 Jul;82(5):655-8.
7. Deguchi M, Rapoff AJ, Zdeblick TA. Posterolateral fusion for isthmic spondylolisthesis in adults: analysis of fusion rate and clinical results. J Spinal Disord. 1998 Dec;11(6):459-64.
8. Glassman SD, Rose SM, Dimar JR, Puno RM, Campbell MJ, Johnson JR. The effect of postoperative nonsteroidal anti-inflammatory drug administration on spinal fusion. Spine (Phila Pa 1976). 1998 Apr 1;23(7):834-8.
9. Jeffcoach DR, Sams VG, Lawson CM, Enderson BL, Smith ST, Kline H, Barlow PB, Wylie DR, Krumenacker LA, McMillen JC, Pyda J, Daley BJ; University of Tennessee Medical Center, Department of Surgery. Nonsteroidal anti-inflammatory drugs’ impact on nonunion and infection rates in long-bone fractures. J Trauma Acute Care Surg. 2014 Mar;76(3):779-83.
10. Sagi HC, Jordan CJ, Barei DP, Serrano-Riera R, Steverson B. Indomethacin prophylaxis for heterotopic ossification after acetabular fracture surgery increases the risk for nonunion of the posterior wall. J Orthop Trauma. 2014 Jul;28(7):377-83.
11. Lumawig JM, Yamazaki A, Watanabe K. Dose-dependent inhibition of diclofenac sodium on posterior lumbar interbody fusion rates. Spine J. 2009 May;9(5):343-9. Epub 2008 Sep 14.
12. Davis TR, Ackroyd CE. Non-steroidal anti-inflammatory agents in the management of Colles’ fractures. Br J Clin Pract. 1988 May;42(5):184-9.
13. Adolphson P, Abbaszadegan H, Jonsson U, Dalén N, Sjöberg HE, Kalén 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.
14. 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 Sep 1;33(19):2079-82.
15. Bhattacharyya T, Levin R, Vrahas MS, Solomon DH. Nonsteroidal antiinflammatory drugs and nonunion of humeral shaft fractures. Arthritis Rheum. 2005 Jun 15;53(3):364-7.
16. Dumont AS, Verma S, Dumont RJ, Hurlbert RJ. Nonsteroidal anti-inflammatory drugs and bone metabolism in spinal fusion surgery: a pharmacological quandary. J Pharmacol Toxicol Methods. 2000 Jan-Feb;43(1):31-9.
17. Harder AT, An YH. The mechanisms of the inhibitory effects of nonsteroidal anti-inflammatory drugs on bone healing: a concise review. J Clin Pharmacol. 2003 Aug;43(8):807-15.
    18. Bandolier Extra. NSAIDs, coxibs, smoking and bone. 2004 Mar. http://www.medicine.ox.ac.uk/bandolier/booth/painpag/wisdom/nsb.pdf. Accessed 2015 Aug 5.
      19. Thaller J, Walker M, Kline AJ, Anderson DG. The effect of nonsteroidal anti-inflammatory agents on spinal fusion. Orthopedics. 2005 Mar;28(3):299-303, quiz :304-5.
        20. Radi ZA, Khan NK. Effects of cyclooxygenase inhibition on bone, tendon, and ligament healing. Inflamm Res. 2005 Sep;54(9):358-66.
          21. Vuolteenaho K, Moilanen T, Moilanen E. Non-steroidal anti-inflammatory drugs, cyclooxygenase-2 and the bone healing process. Basic Clin Pharmacol Toxicol. 2008 Jan;102(1):10-4. Epub 2007 Oct 31.
          22. Gaston MS, Simpson AH. Inhibition of fracture healing. J Bone Joint Surg Br. 2007 Dec;89(12):1553-60.
            23. Pountos I, Georgouli T, Blokhuis TJ, Pape HC, Giannoudis PV. Pharmacological agents and impairment of fracture healing: what is the evidence? Injury. 2008 Apr;39(4):384-94. Epub 2008 Mar 7.
              24. Boursinos LA, Karachalios T, Poultsides L, Malizos KN. Do steroids, conventional non-steroidal anti-inflammatory drugs and selective Cox-2 inhibitors adversely affect fracture healing? J Musculoskelet Neuronal Interact. 2009 Jan-Mar;9(1):44-52.
                25. Xian CJ, Zhou XF. Treating skeletal pain: limitations of conventional anti-inflammatory drugs, and anti-neurotrophic factor as a possible alternative. Nat Clin Pract Rheumatol. 2009 Feb;5(2):92-8.
                  26. Barry S. Non-steroidal anti-inflammatory drugs inhibit bone healing: a review. Vet Comp Orthop Traumatol. 2010;23(6):385-92. Epub 2010 Sep 9.
                    27. Dodwell ER, Latorre JG, Parisini E, Zwettler E, Chandra D, Mulpuri K, Snyder B. NSAID exposure and risk of nonunion: a meta-analysis of case-control and cohort studies. Calcif Tissue Int. 2010 Sep;87(3):193-202. Epub 2010 Jun 15.
                    28. Li Q, Zhang Z, Cai Z. High-dose ketorolac affects adult spinal fusion: a meta-analysis of the effect of perioperative nonsteroidal anti-inflammatory drugs on spinal fusion. Spine (Phila Pa 1976). 2011 Apr 1;36(7):E461-8.
                    29. Pountos I, Georgouli T, Calori GM, Giannoudis PV. Do nonsteroidal anti-inflammatory drugs affect bone healing? A critical analysis. ScientificWorldJournal. 2012;2012:606404. Epub 2012 Jan 4.
                    30. Kurmis AP, Kurmis TP, O’Brien JX, Dalén T. The effect of nonsteroidal anti-inflammatory drug administration on acute phase fracture-healing: a review. J Bone Joint Surg Am. 2012 May 2;94(9):815-23.
                    31. van Esch RW, Kool MM, van As S. NSAIDs can have adverse effects on bone healing. Med Hypotheses. 2013 Aug;81(2):343-6. Epub 2013 May 13.
                    32. Su B, O’Connor JP. NSAID therapy effects on healing of bone, tendon, and the enthesis. J Appl Physiol (1985). 2013 Sep;115(6):892-9. Epub 2013 Jul 18.
                    33. Geusens P, Emans PJ, de Jong JJ, van den Bergh J. NSAIDs and fracture healing. Curr Opin Rheumatol. 2013 Jul;25(4):524-31.
                    34. Abdul-Hadi O, Parvizi J, Austin MS, Viscusi E, Einhorn T. Nonsteroidal anti-inflammatory drugs in orthopaedics. J Bone Joint Surg Am. 2009 Aug;91(8):2020-7.
                      35. Cottrell J, O’Connor JP. Effect of non-steroidal anti-inflammatory drugs on bone healing. Pharmaceuticals (Ott). 2010;3:1668-93.
                      36. Ziltener JL, Leal S, Fournier PE. Non-steroidal anti-inflammatory drugs for athletes: an update. Ann Phys Rehabil Med. 2010 May;53(4):278-82: 282-8. Epub 2010 Mar 20.
                        37. Wheeler P, Batt ME. Do non-steroidal anti-inflammatory drugs adversely affect stress fracture healing? A short review. Br J Sports Med. 2005 Feb;39(2):65-9.
                        38. Gajraj NM. The effect of cyclooxygenase-2 inhibitors on bone healing. Reg Anesth Pain Med. 2003 Sep-Oct;28(5):456-65.
                          39. Dahners LE, Mullis BH. Effects of nonsteroidal anti-inflammatory drugs on bone formation and soft-tissue healing. J Am Acad Orthop Surg. 2004 May-Jun;12(3):139-43.
                          40. Austin MS, Abdul-Hadi O, Parvizi J, Viscusi ER, Einhorn T. Cyclooxygenase-2 inhibitors and other nonsteroidal anti-inflammatory drugs in the treatment of musculoskeletal conditions. Instr Course Lect. 2009;58:759-68.
                          41. Aspenberg P. Drugs and fracture repair. Acta Orthop. 2005 Dec;76(6):741-8.
                          42. Clarke S, Lecky F. Best evidence topic report. Do non-steroidal anti-inflammatory drugs cause a delay in fracture healing? Emerg Med J. 2005 Sep;22(9):652-3.
                          43. Taylor IC, Lindblad AJ, Kolber MR. Fracture healing and NSAIDs. Can Fam Physician. 2014 Sep;60(9):817: e439-40.
                          44. Aspenberg P. Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs. J Orthop Res. 2004 May;22(3):684, author reply: 685.
                            45. Kjaersgaard-Andersen P, Jensen K. Cox inhibitors and bone healing. Acta Orthop Scand. 2003 Apr;74(2):230-1, author reply: 231.
                              46. Einhorn TA. Cox-2: Where are we in 2003? - The role of cyclooxygenase-2 in bone repair. Arthritis Res Ther. 2003;5(1):5-7. Epub 2002 Oct 21.
                                47. Hochberg MC, Melin JM, Reicin A. Cox-2 inhibitors and fracture healing: an argument against such an effect. J Bone Miner Res. 2003 Mar;18(3):583, author reply :584-7.
                                48. American Academy of Orthopaedic Surgeons. Goodman SB, Boyan BD. COX-2 inhibitors and bone: 2005 update. 2005. http://www2.aaos.org/bulletin/jun05/cover.asp. Accessed 2015 Aug 5.
                                49. Gerstenfeld LC, Einhorn TA. COX inhibitors and their effects on bone healing. Expert Opin Drug Saf. 2004 Mar;3(2):131-6.
                                50. Aspenberg P. Avoid cox inhibitors after skeletal surgery! Acta Orthop Scand. 2002 Oct;73(5):489-90.
                                51. Einhorn TA. Do inhibitors of cyclooxygenase-2 impair bone healing? J Bone Miner Res. 2002 Jun;17(6):977-8.
                                52. Do Schoene ML. Cox‐2 agents and other NSAIDs inhibit fracture healing and bone ingrowth? Lippincott’s Bone and Joint Newsletter. 2002;8(7):75-6.
                                53. Review: Paucity of high-quality studies on impact of NSAIDs on bony healing. Lippincott’s Bone and Joint Newsletter. 2002;8(7):76.
                                54. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009 Jul 21;339:b2535.
                                55. Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, Gøtzsche PC, Lang T; CONSORT GROUP (Consolidated Standards of Reporting Trials). The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med. 2001 Apr 17;134(8):663-94.
                                56. Coleman BD, Khan KM, Maffulli N, Cook JL, Wark JD; Victorian Institute of Sport Tendon Study Group. Studies of surgical outcome after patellar tendinopathy: clinical significance of methodological deficiencies and guidelines for future studies. Scand J Med Sci Sports. 2000 Feb;10(1):2-11.
                                57. Jakobsen RB, Engebretsen L, Slauterbeck JR. An analysis of the quality of cartilage repair studies. J Bone Joint Surg Am. 2005 Oct;87(10):2232-9.
                                58. Sambandam SN, Gul A, Priyanka P. Analysis of methodological deficiencies of studies reporting surgical outcome following cemented total-joint arthroplasty of trapezio-metacarpal joint of the thumb. Int Orthop. 2007 Oct;31(5):639-45. Epub 2006 Sep 23.
                                59. Cowan J, Lozano-Calderón S, Ring D. Quality of prospective controlled randomized trials. Analysis of trials of treatment for lateral epicondylitis as an example. J Bone Joint Surg Am. 2007 Aug;89(8):1693-9.
                                60. Sinatra RS, Torres J, Bustos AM. Pain management after major orthopaedic surgery: current strategies and new concepts. J Am Acad Orthop Surg. 2002 Mar-Apr;10(2):117-29.
                                61. Joshi GP, Beck DE, Emerson RH, Halaszynski TM, Jahr JS, Lipman AG, Nihira MA, Sheth KR, Simpson MH, Sinatra RS. Defining new directions for more effective management of surgical pain in the United States: highlights of the inaugural Surgical Pain Congress™. Am Surg. 2014 Mar;80(3):219-28.
                                62. Schroer WC, Diesfeld PJ, LeMarr AR, Reedy ME. Benefits of prolonged postoperative cyclooxygenase-2 inhibitor administration on total knee arthroplasty recovery: a double-blind, placebo-controlled study. J Arthroplasty. 2011 Sep;26(6)(Suppl):2-7. Epub 2011 Jul 1.
                                63. Meunier A, Aspenberg P, Good L. Celecoxib does not appear to affect prosthesis fixation in total knee replacement: A randomized study using radiostereometry in 50 patients. Acta Orthop. 2009 Feb;80(1):46-50.
                                  64. Meunier A, Lisander B, Good L. Effects of celecoxib on blood loss, pain, and recovery of function after total knee replacement: a randomized placebo-controlled trial. Acta Orthop. 2007 Oct;78(5):661-7.
                                    65. De Oliveira GS Jr, Agarwal D, Benzon HT. Perioperative single dose ketorolac to prevent postoperative pain: a meta-analysis of randomized trials. Anesth Analg. 2012 Feb;114(2):424-33. Epub 2011 Sep 29.
                                    66. Manchikanti L, Helm S 2nd, Fellows B, Janata JW, Pampati V, Grider JS, Boswell MV. Opioid epidemic in the United States. Pain Physician. 2012 Jul;15(3)(Suppl):ES9-38.
                                    67. O’Connor JP, Manigrasso MB, Kim BD, Subramanian S. Fracture healing and lipid mediators. Bonekey Rep. 2014 Apr 2;3:517.
                                    68. Hankenson KD, Zimmerman G, Marcucio R. Biological perspectives of delayed fracture healing. Injury. 2014 Jun;45(Suppl 2):S8-15.
                                      69. 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.
                                      70. Arikawa T, Omura K, Morita I. Regulation of bone morphogenetic protein-2 expression by endogenous prostaglandin E2 in human mesenchymal stem cells. J Cell Physiol. 2004 Sep;200(3):400-6.
                                      71. Jurado S, Garcia-Giralt N, Díez-Pérez A, Esbrit P, Yoskovitz G, Agueda L, Urreizti R, Pérez-Edo L, Saló G, Mellibovsky L, Balcells S, Grinberg D, Nogués X. Effect of IL-1beta, PGE(2), and TGF-beta1 on the expression of OPG and RANKL in normal and osteoporotic primary human osteoblasts. J Cell Biochem. 2010 May 15;110(2):304-10.
                                        72. Marsell R, Einhorn TA. The biology of fracture healing. Injury. 2011 Jun;42(6):551-5. Epub 2011 Apr 13.
                                          73. Coetzee M, Haag M, Joubert AM, Kruger MC. Effects of arachidonic acid, docosahexaenoic acid and prostaglandin E(2) on cell proliferation and morphology of MG-63 and MC3T3-E1 osteoblast-like cells. Prostaglandins Leukot Essent Fatty Acids. 2007 Jan;76(1):35-45. Epub 2006 Nov 17.
                                          74. Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev. 1999 Oct;79(4):1193-226.
                                          75. Tsutsumi R, Xie C, Wei X, Zhang M, Zhang X, Flick LM, Schwarz EM, O’Keefe RJ. PGE2 signaling through the EP4 receptor on fibroblasts upregulates RANKL and stimulates osteolysis. J Bone Miner Res. 2009 Oct;24(10):1753-62.
                                            76. Zhang M, Ho HC, Sheu TJ, Breyer MD, Flick LM, Jonason JH, Awad HA, Schwarz EM, O’Keefe RJ. EP1(-/-) mice have enhanced osteoblast differentiation and accelerated fracture repair. J Bone Miner Res. 2011 Apr;26(4):792-802.
                                              77. Xie C, Liang B, Xue M, Lin AS, Loiselle A, Schwarz EM, Guldberg RE, O’Keefe RJ, Zhang X. Rescue of impaired fracture healing in COX-2-/- mice via activation of prostaglandin E2 receptor subtype 4. Am J Pathol. 2009 Aug;175(2):772-85. Epub 2009 Jul 23.
                                              78. Nunamaker DM. Experimental models of fracture repair. Clin Orthop Relat Res. 1998 Oct;(355)(Suppl):S56-65.
                                              79. O’Loughlin PF, Morr S, Bogunovic L, Kim AD, Park B, Lane JM. Selection and development of preclinical models in fracture-healing research. J Bone Joint Surg Am. 2008 Feb;90(Suppl 1):79-84.
                                              80. Lau KH, Kothari V, Das A, Zhang XB, Baylink DJ. Cellular and molecular mechanisms of accelerated fracture healing by COX2 gene therapy: studies in a mouse model of multiple fractures. Bone. 2013 Apr;53(2):369-81. Epub 2013 Jan 11.
                                              81. Rundle CH, Strong DD, Chen ST, Linkhart TA, Sheng MH, Wergedal JE, Lau KH, Baylink DJ. Retroviral-based gene therapy with cyclooxygenase-2 promotes the union of bony callus tissues and accelerates fracture healing in the rat. J Gene Med. 2008 Mar;10(3):229-41.
                                              82. Ho ML, Chang JK, Wang GJ. Effects of ketorolac on bone repair: A radiographic study in modeled demineralized bone matrix grafted rabbits. Pharmacology. 1998 Sep;57(3):148-59.
                                              83. Krischak GD, Augat P, Sorg T, Blakytny R, Kinzl L, Claes L, Beck A. Effects of diclofenac on periosteal callus maturation in osteotomy healing in an animal model. Arch Orthop Trauma Surg. 2007 Jan;127(1):3-9. Epub 2006 Jul 25.
                                              84. Goodman SB, Ma T, Mitsunaga L, Miyanishi K, Genovese MC, Smith RL. Temporal effects of a COX-2-selective NSAID on bone ingrowth. J Biomed Mater Res A. 2005 Mar 1;72(3):279-87.
                                              85. Simon AM, Manigrasso MB, O’Connor JP. Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner Res. 2002 Jun;17(6):963-76.
                                              86. Lindholm TS, Törnkvist 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.
                                                87. Mullis BH, Copland ST, Weinhold PS, Miclau T, Lester GE, Bos GD. Effect of COX-2 inhibitors and non-steroidal anti-inflammatory drugs on a mouse fracture model. Injury. 2006 Sep;37(9):827-37. Epub 2006 Feb 23.
                                                  88. Bergenstock M, Min W, Simon AM, Sabatino C, O’Connor JP. A comparison between the effects of acetaminophen and celecoxib on bone fracture healing in rats. J Orthop Trauma. 2005 Nov-Dec;19(10):717-23.
                                                    89. O’Connor JP, Capo JT, Tan V, Cottrell JA, Manigrasso MB, Bontempo N, Parsons JR. A comparison of the effects of ibuprofen and rofecoxib on rabbit fibula osteotomy healing. Acta Orthop. 2009 Oct;80(5):597-605.
                                                      90. Dimar JR 2nd, Ante WA, Zhang YP, Glassman SD. The effects of nonsteroidal anti-inflammatory drugs on posterior spinal fusions in the rat. Spine (Phila Pa 1976). 1996 Aug 15;21(16):1870-6.
                                                      91. Gerstenfeld LC, Al-Ghawas M, Alkhiary YM, Cullinane DM, Krall EA, Fitch JL, Webb EG, Thiede MA, Einhorn TA. Selective and nonselective cyclooxygenase-2 inhibitors and experimental fracture-healing. Reversibility of effects after short-term treatment. J Bone Joint Surg Am. 2007 Jan;89(1):114-25.
                                                      92. Giannoudis PV, Smith RM, Bellamy MC, Morrison JF, Dickson RA, Guillou PJ. Stimulation of the inflammatory system by reamed and unreamed nailing of femoral fractures. An analysis of the second hit. J Bone Joint Surg Br. 1999 Mar;81(2):356-61.
                                                      93. Lasanianos NG, Kanakaris NK, Giannoudis PV. Intramedullary nailing as a ‘second hit’ phenomenon in experimental research: lessons learned and future directions. Clin Orthop Relat Res. 2010 Sep;468(9):2514-29. Epub 2009 Dec 10.
                                                      94. Mundi R, Chaudhry H, Mundi S, Godin K, Bhandari M. Design and execution of clinical trials in orthopaedic surgery. Bone Joint Res. 2014 May;3(5):161-8.
                                                      95. Green BN, Johnson CD, Adams A. Writing narrative literature reviews for peer-reviewed journals: secrets of the trade. J Chiropr Med. 2006 Fall;5(3):101-17.
                                                      96. Sucato DJ, Lovejoy JF, Agrawal S, Elerson E, Nelson T, McClung A. Postoperative ketorolac does not predispose to pseudoarthrosis following posterior spinal fusion and instrumentation for adolescent idiopathic scoliosis. Spine (Phila Pa 1976). 2008 May 1;33(10):1119-24.
                                                      97. Vitale MG, Choe JC, Hwang MW, Bauer RM, Hyman JE, Lee FY, Roye DP Jr. Use of ketorolac tromethamine in children undergoing scoliosis surgery. an analysis of complications. Spine J. 2003 Jan-Feb;3(1):55-62.
                                                      98. Kay RM, Directo MP, Leathers M, Myung K, Skaggs DL. Complications of ketorolac use in children undergoing operative fracture care. J Pediatr Orthop. 2010 Oct-Nov;30(7):655-8.
                                                        99. Drendel AL, Gorelick MH, Weisman SJ, Lyon R, Brousseau DC, Kim MK. A randomized clinical trial of ibuprofen versus acetaminophen with codeine for acute pediatric arm fracture pain. Ann Emerg Med. 2009 Oct;54(4):553-60. Epub 2009 Aug 19.
                                                          100. Horn PL, Wrona S, Beebe AC, Klamar JE. A retrospective quality improvement study of ketorolac use following spinal fusion in pediatric patients. Orthop Nurs. 2010 Sep-Oct;29(5):342-3.
                                                          101. Reuben SS, Ablett D, Kaye R. High dose nonsteroidal anti-inflammatory drugs compromise spinal fusion. Can J Anaesth. 2005 May;52(5):506-12.
                                                          102. van Staa TP, Leufkens HG, Cooper C. Use of nonsteroidal anti-inflammatory drugs and risk of fractures. Bone. 2000 Oct;27(4):563-8.
                                                          103. Bauer DC, Orwoll ES, Fox KM, Vogt TM, Lane NE, Hochberg MC, Stone K, Nevitt MC; Study of Osteoporotic Fractures Research Group. Aspirin and NSAID use in older women: effect on bone mineral density and fracture risk. J Bone Miner Res. 1996 Jan;11(1):29-35.
                                                          104. Vitale MG, Levy DE, Johnson MG, Gelijns AC, Moskowitz AJ, Roye BP, Verdisco L, Roye DP Jr. Assessment of quality of life in adolescent patients with orthopaedic problems: are adult measures appropriate? J Pediatr Orthop. 2001 Sep-Oct;21(5):622-8.
                                                          105. Burd TA, Lowry KJ, Anglen JO. Indomethacin compared with localized irradiation for the prevention of heterotopic ossification following surgical treatment of acetabular fractures. J Bone Joint Surg Am. 2001 Dec;83(12):1783-8.
                                                          106. McLaren AC. Prophylaxis with indomethacin for heterotopic bone. After open reduction of fractures of the acetabulum. J Bone Joint Surg Am. 1990 Feb;72(2):245-7.
                                                            107. Moore KD, Goss K, Anglen JO. Indomethacin versus radiation therapy for prophylaxis against heterotopic ossification in acetabular fractures: a randomised, prospective study. J Bone Joint Surg Br. 1998 Mar;80(2):259-63.
                                                            108. Reuben SS, Ekman EF. The effect of cyclooxygenase-2 inhibition on analgesia and spinal fusion. J Bone Joint Surg Am. 2005 Mar;87(3):536-42.
                                                            109. Spindler KP, Kuhn JE, Dunn W, Matthews CE, Harrell FE Jr, Dittus RS. Reading and reviewing the orthopaedic literature: a systematic, evidence-based medicine approach. J Am Acad Orthop Surg. 2005 Jul-Aug;13(4):220-9.
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