Faculty Bibliography

Importance: Failure of bone fracture healing occurs in 5% to 10% of all patients. Nonunion risk is associated with the severity of injury and with the surgical treatment technique, yet progression to nonunion is not fully explained by these risk factors. Objective: To test a hypothesis that fracture characteristics and patient-related risk factors assessable by the clinician at patient presentation can indicate the probability of fracture nonunion. Design, Setting, and Participants: An inception cohort study in a large payer database of patients with fracture in the United States was conducted using patient-level health claims for medical and drug expenses compiled for approximately 90.1 million patients in calendar year 2011. The final database collated demographic descriptors, treatment procedures as per Current Procedural Terminology codes; comorbidities as per International Classification of Diseases, Ninth Revision codes; and drug prescriptions as per National Drug Code Directory codes. Logistic regression was used to calculate odds ratios (ORs) for variables associated with nonunion. Data analysis was performed from January 1, 2011, to December 31, 2012. Exposures: Continuous enrollment in the database was required for 12 months after fracture to allow sufficient time to capture a nonunion diagnosis. Results: The final analysis of 309330 fractures in 18 bones included 178 952 women (57.9%); mean (SD) age was 44.48 (13.68) years. The nonunion rate was 4.9%. Elevated nonunion risk was associated with severe fracture (eg, open fracture, multiple fractures), high body mass index, smoking, and alcoholism. Women experienced more fractures, but men were more prone to nonunion. The nonunion rate also varied with fracture location: scaphoid, tibia plus fibula, and femur were most likely to be nonunion. The ORs for nonunion fractures were significantly increased for risk factors, including number of fractures (OR, 2.65; 95% CI, 2.34-2.99), use of nonsteroidal anti-inflammatory drugs plus opioids (OR, 1.84; 95% CI, 1.73-1.95), operative treatment (OR, 1.78; 95% CI, 1.69-1.86), open fracture (OR, 1.66; 95% CI, 1.55-1.77), anticoagulant use (OR, 1.58; 95% CI, 1.51-1.66), osteoarthritis with rheumatoid arthritis (OR, 1.58; 95% CI, 1.38-1.82), anticonvulsant use with benzodiazepines (OR, 1.49; 95% CI, 1.36-1.62), opioid use (OR, 1.43; 95% CI, 1.34-1.52), diabetes (OR, 1.40; 95% CI, 1.21-1.61), high-energy injury (OR, 1.38; 95% CI, 1.27-1.49), anticonvulsant use (OR, 1.37; 95% CI, 1.31-1.43), osteoporosis (OR, 1.24; 95% CI, 1.14-1.34), male gender (OR, 1.21; 95% CI, 1.16-1.25), insulin use (OR, 1.21; 95% CI, 1.10-1.31), smoking (OR, 1.20; 95% CI, 1.14-1.26), benzodiazepine use (OR, 1.20; 95% CI, 1.10-1.31), obesity (OR, 1.19; 95% CI, 1.12-1.25), antibiotic use (OR, 1.17; 95% CI, 1.13-1.21), osteoporosis medication use (OR, 1.17; 95% CI, 1.08-1.26), vitamin D deficiency (OR, 1.14; 95% CI, 1.05-1.22), diuretic use (OR, 1.13; 95% CI, 1.07-1.18), and renal insufficiency (OR, 1.11; 95% CI, 1.04-1.17) (multivariate P < .001 for all). Conclusions and Relevance: The probability of fracture nonunion can be based on patient-specific risk factors at presentation. Risk of nonunion is a function of fracture severity, fracture location, disease comorbidity, and medication use.

OBJECTIVE: To determine whether low intensity pulsed ultrasound (LIPUS), compared with sham treatment, accelerates functional recovery and radiographic healing in patients with operatively managed tibial fractures. DESIGN: A concealed, randomized, blinded, sham controlled clinical trial with a parallel group design of 501 patients, enrolled between October 2008 and September 2012, and followed for one year. SETTING: 43 North American academic trauma centers. PARTICIPANTS: Skeletally mature men or women with an open or closed tibial fracture amenable to intramedullary nail fixation. Exclusions comprised pilon fractures, tibial shaft fractures that extended into the joint and required reduction, pathological fractures, bilateral tibial fractures, segmental fractures, spiral fractures >7.5 cm in length, concomitant injuries that were likely to impair function for at least as long as the patient's tibial fracture, and tibial fractures that showed <25% cortical contact and >1 cm gap after surgical fixation. 3105 consecutive patients who underwent intramedullary nailing for tibial fracture were assessed, 599 were eligible and 501 provided informed consent and were enrolled. INTERVENTIONS: Patients were allocated centrally to self administer daily LIPUS (n=250) or use a sham device (n=251) until their tibial fracture showed radiographic healing or until one year after intramedullary fixation. MAIN OUTCOME MEASURES: Primary registry specified outcome was time to radiographic healing within one year of fixation; secondary outcome was rate of non-union. Additional protocol specified outcomes included short form-36 (SF-36) physical component summary (PCS) scores, return to work, return to household activities, return to >/=80% of function before injury, return to leisure activities, time to full weight bearing, scores on the health utilities index (mark 3), and adverse events related to the device. RESULTS: SF-36 PCS data were acquired from 481/501 (96%) patients, for whom we had 2303/2886 (80%) observations, and radiographic healing data were acquired from 482/501 (96%) patients, of whom 82 were censored. Results showed no impact on SF-36 PCS scores between LIPUS and control groups (mean difference 0.55, 95% confidence interval -0.75 to 1.84; P=0.41) or for the interaction between time and treatment (P=0.30); minimal important difference is 3-5 points) or in other functional measures. There was also no difference in time to radiographic healing (hazard ratio 1.07, 95% confidence interval 0.86 to 1.34; P=0.55). There were no differences in safety outcomes between treatment groups. Patient compliance was moderate; 73% of patients administered >/=50% of all recommended treatments. CONCLUSIONS: Postoperative use of LIPUS after tibial fracture fixation does not accelerate radiographic healing and fails to improve functional recovery.Study registration ClinicalTrialGov Identifier: NCT00667849.

Electrical stimulation is a common adjunct used to promote bone healing; its efficacy, however, remains uncertain. We conducted a meta-analysis of randomized sham-controlled trials to establish the efficacy of electrical stimulation for bone healing. We identified all trials randomizing patients to electrical or sham stimulation for bone healing. Outcomes were pain relief, functional improvement, and radiographic nonunion. Two reviewers assessed eligibility and risk of bias, performed data extraction, and rated the quality of the evidence. Fifteen trials met our inclusion criteria. Moderate quality evidence from 4 trials found that stimulation produced a significant improvement in pain (mean difference (MD) on 100-millimeter visual analogue scale = -7.7 mm; 95% CI -13.92 to -1.43; p = 0.02). Two trials found no difference in functional outcome (MD = -0.88; 95% CI -6.63 to 4.87; p = 0.76). Moderate quality evidence from 15 trials found that stimulation reduced radiographic nonunion rates by 35% (95% CI 19% to 47%; number needed to treat = 7; p < 0.01). Patients treated with electrical stimulation as an adjunct for bone healing have less pain and are at reduced risk for radiographic nonunion; functional outcome data are limited and requires increased focus in future trials.

Delayed fracture healing and nonunion occurs in up to 5-10% of all fractures, and can present a challenging clinical scenario for the treating physician. Methods for the enhancement of skeletal repair may benefit patients that are at risk of, or have experienced, delayed healing or nonunion. These methods can be categorized into either physical stimulation therapies or biological therapies. Physical stimulation therapies include electrical stimulation, low-intensity pulsed ultrasonography, or extracorporeal shock wave therapy. Biological therapies can be further classified into local or systemic therapy based on the method of delivery. Local methods include autologous bone marrow, autologous bone graft, fibroblast growth factor-2, platelet-rich plasma, platelet-derived growth factor, and bone morphogenetic proteins. Systemic therapies include parathyroid hormone and bisphosphonates. This article reviews the current applications and supporting evidence for the use of these therapies in the enhancement of fracture healing.

OBJECTIVES: The purpose of this study is to characterize demographics, healing time and complications of a large series of operatively treated atypical femur fractures. DESIGN: Retrospective multicenter review. SETTING: 17 academic medical centers. PATIENTS: Bisphosphonate related fractures as defined by ASBMR. Fractures had to be followed for at least 6 months or to union or revision. INTERVENTION: Operative treatment of bisphosphonate related fracture. MAIN OUTCOME MEASUREMENTS: Union time and complications of treatment, as well as information about the contralateral limb. RESULTS: There were 179 patients, average age 72, average BMI 27.2. Average followup was 17 months. Twenty-one percent had a prior history of fragility fracture; 34% had prodromal pain. Most (88%) lived independently before injury. Thirty-one percent had radiographic changes suggesting stress reaction. Surgical fixation was with cephalomedullary nail (51%), IM nail (48%) or plate (1%). Complications included death (4), PE (3), and wound infection (6). Twenty (12%) patients underwent revision at an average of 11 months. Excluding revisions, average union time was 5.2 months. For revisions, union occurred at an average of 10.2 months after intervention. No association was identified between discontinuation of bisphosphonates and union time (P =0.5) or need for revision (P =0.7). Twenty-one percent sustained contralateral femur fractures; 32% of these had pain and 59% had stress reaction prior to contralateral fracture. CONCLUSIONS: In this series, surgery had a 12% failure rate and delayed average time to union. Twenty-one percent developed contralateral femur fractures within 2 years, underscoring the need to evaluate the contralateral extremity. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Aseptic loosening is a major complication of prosthetic joint surgery, characterized by chronic inflammation, pain, and osteolysis surrounding the bone-implant interface. Progranulin (PGRN) is known to have anti-inflammatory action by binding to Tumor Necrosis Factor (TNF) receptors and antagonizing TNFalpha. Here we report that titanium particles significantly induced PGRN expression in RAW264.7 cells and also in a mouse air-pouch model of inflammation. PGRN-deficiency enhanced, whereas administration of recombinant PGRN effectively inhibited, titanium particle-induced inflammation in an air pouch model. In addition, PGRN also significantly inhibited titanium particle-induced osteoclastogenesis and calvarial osteolysis in vitro, ex vivo and in vivo. Mechanistic studies demonstrated that the inhibition of PGRN on titanium particle induced-inflammation is primarily via neutralizing the titanium particle-activated TNFalpha/NF-kappaB signaling pathway and this is evidenced by the suppression of particle-induced IkappaB phosphorylation, NF-kappaB p65 nuclear translocation, and activity of the NF-kappaB-specific reporter gene. Collectively, these findings not only demonstrate that PGRN plays an important role in inhibiting titanium particle-induced inflammation, but also provide a potential therapeutic agent for the prevention of wear debris-induced inflammation and osteolysis.

PURPOSE: This consensus review article considers the question of whether glucocorticoid (GC) therapy is still relevant in the treatment of rheumatic diseases, with a particular focus on rheumatoid arthritis (RA), and whether its side effects can be adequately managed. Recent basic and clinical research on the molecular, cellular and clinical effects of GCs have considerably advanced our knowledge in this field. An overview of the subject seems appropriate. METHODS: This review is the result of a multidisciplinary expert working group, organised by European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. The recent literature was surveyed and the salient evidence synthetized. RESULTS: The pathophysiological basis of RA (and other inflammatory rheumatic diseases) now strongly implicates the adaptive immune system in addition to innate mechanisms. The molecular effect of GCs and differential GC sensitivity is better understood, although exploiting this knowledge is still in its infancy. The newer treatment strategies of early and aggressive control of RA have gr eatly improved clinical outcomes, but improvements are still possible. Newer targeted anti-inflammatory drugs have made an important impact, yet they too are associated with numerous side effects. DISCUSSION: Short durations of moderate doses of GCs are generally well tolerated and have a positive benefit/risk ratio. Patients should be assessed for fracture risk and bone preserving agents and be prescribed calcium and vitamin D supplementation. CONCLUSIONS: Within a strategy of a disease modifying approach to inflammatory disease, combination therapy including a GC is effective approach.

INTRODUCTION: Biologic risk factors have a significant impact on fracture healing, but most factors cannot be mitigated. Patient medications are unusual in that they have a significant impact on fracture healing and can potentially be adjusted by a physician after fracture. We hypothesize that risk associated with medications accrues to chronic use prior to fracture. METHODS: Patient-level health claims for medical and drug expenses were compiled for -90.1 million patients. Study inclusion was limited to patients with a coded bone fracture in calendar year 2011, with continuous enrollment for 1 month prior and 12 months after fracture, to allow time to assess chronic medication use. Chronic medication use was defined as medication use >30 days prior to fracture with continued use after fracture. The final database contained 268,784 fractures, with demographic descriptors, treatment procedures per Current Procedural Terminology (CPT) codes, co-morbidities per International Statistical Classification of Diseases and Related Health Problems (ICD-9) codes, and drug prescriptions per National Drug Code Directory (Red Book) codes. Logistic regression was used to calculate odds ratios for nonunion associated with chronic use of medications. This study was exempted from ethical approval by the Institutional Review Board of Duke University Medical Center because patient data were completely de-identified. RESULTS: A total of 43,727 fractures (16.3% of 268,784 fractures) affected patients using chronic pain medications (Table 1). The nonunion rate among chronic pain medication users was 7.35%, while the nonunion rate among non-chronic pain medication users was 4.04% (P < 0.001). The nonunion rate in non-chronic pain medication users was equivalent to the overall rate of nonunion in an epidemiologic study of fracture patients [ 1 ]. Chronic pain medication users were significantly more prone (p < 0.001) to nonunion at every age and in both genders, and chronic pain medication use increased the rate of nonunion rate associated with multiple fractures, past or current smoking, or diagnosed alcoholism (Table 1). Chronic use of opioid agonists, opioid partial agonists, salicylates, prescription NSAIDs, unclassified NSAIDs, benzodiazepine, and miscellaneous anticonvulsants significantly increased risk of nonunion in 18 bones (all, multivariate p < 0.001). Nonunion risk was also significantly increased by chronic use of antibiotics (cephalosporin, erythromycin/ macrolides, penicillin, miscellaneous), cardiac medications (antiplatelet agents, ACE inhibitors, beta blockers, calcium channel blockers, unclassified medications), and anticoagulants (all, multivariate p < 0.001). Conversely, non-chronic medication use, even of opioid analgesics, prescription NSAIDs, and anticonvulsants, did not increase nonunion risk. Oral contraceptive use was protective from nonunion (p < 0.001). DISCUSSION: Physicians concerned with fracture nonunion risk should consider counseling patients to avoid chronic medications such as opioids, prescription NSAIDs, anticonvulsants, some cardiac medications, and anticoagulants. SIGNIFICANCE: Our results suggest that chronic medication use is a significant and substantial risk factor for fracture nonunion. It is critical that trauma surgeons be aware of the nonunion risk created by medication use because trauma patients may represent a population enriched for nonunion risk factors. In fact, warning signs of pain medication abuse may ultimately be risk factors for fracture nonunion