Faculty Bibliography

Chronic use of selective serotonin re-uptake inhibitors (SSRI) for the treatment of depression has been linked to osteoporosis. In this study, we investigated the effect of chronic SSRI use on fracture healing in two murine models of bone regeneration. First, we performed a comprehensive analysis of endochondral bone healing in a femur fracture model. C57/BL6 mice treated with fluoxetine, the most commonly prescribed SSRI, developed a normal cartilaginous soft-callus at 14 days after fracture and demonstrated a significantly smaller and biomechanically weaker bony hard-callus at 28 days. In order to further dissect the mechanism that resulted in a smaller bony regenerate, we used an intramembranous model of bone healing and revealed that fluoxetine treatment resulted in a significantly smaller bony callus at 7 and 14 days post-injury. In order to test whether the smaller bony regenerate following fluoxetine treatment was caused by an inhibition of osteogenic differentiation and/or mineralization, we employed in vitro experiments, which established that fluoxetine treatment decreases osteogenic differentiation and mineralization and that this effect is serotonin-independent. Finally, in a translational approach, we tested whether cessation of the medication would result in restoration of the regenerative potential. However, histologic and microCT analysis revealed non-union formation in these animals with fibrous tissue interposition within the callus. In conclusion, fluoxetine exerts a direct, inhibitory effect on osteoblast differentiation and mineralization, shown in two disparate murine models of bone repair. Discontinuation of the drug did not result in restoration of the healing potential, but rather led to complete arrest of the repair process. Besides the well-established effect of SSRIs on bone homeostasis, our study provides strong evidence that fluoxetine use negatively impacts fracture healing

BACKGROUND: With an expected doubling of the geriatric population within the next thirty years it is becoming increasingly important to determine who among the elderly population benefit from orthopaedic interventions. This study assesses post-operative outcomes in patients aged seventy or greater who sustained a proximal humerus fracture and were treated surgically as compared to a younger geriatric cohort to determine if there is a chronologic age after which post-operative outcomes significantly decline. METHODS: A retrospective chart review was conducted for 201 patients who sustained fractures of the proximal humerus (OTA 11A-C) and were treated operatively by open reduction and internal fixation. Data from 132 independent, active patients aged fifty-five or older was identified and analyzed. Forty-seven patients age 70 or older were compared to 78 patients aged 55-69. Average length of follow-up was 19.5 months. All complications were recorded. Univariate and multivariate analysis was conducted to assess for differences between groups. RESULTS: 95% of patients achieved fracture union within 6 months. No significant differences were found between cohorts with regard to gender, fracture severity, or CCI (p = 0.197, p = 0.276, p = 0.084, respectively). Functional outcome scores, shoulder range of motion, and complications rates for patients aged 70 and older were not significantly different from patients aged 55-69. There were 10 complications in the older elderly cohort (21%), 6 of which required re-operation and 13 complications in the young elderly cohort (17%), 8 of which required re-operation. CONCLUSIONS: Operative fracture repair using locked plating of the proximal humerus in septuagenarians and octogenarians can provide for excellent long-term outcomes in appropriately selected patients. These patients tend to have long term functional outcome scores, post-operative range of motion, and complication rates that are comparable to younger geriatric patients. Physicians should not exclude patients for repair of proximal humerus fractures based on chronological age cutoffs.

AIMS: To evaluate whether an ultra-low-dose CT protocol can diagnose selected limb fractures as well as conventional CT (C-CT). PATIENTS AND METHODS: We prospectively studied 40 consecutive patients with a limb fracture in whom a CT scan was indicated. These were scanned using an ultra-low-dose CT Reduced Effective Dose Using Computed Tomography In Orthopaedic Injury (REDUCTION) protocol. Studies from 16 selected cases were compared with 16 C-CT scans matched for age, gender and type of fracture. Studies were assessed for diagnosis and image quality. Descriptive and reliability statistics were calculated. The total effective radiation dose for each scanned site was compared. RESULTS: The mean estimated effective dose (ED) for the REDUCTION protocol was 0.03 milliSieverts (mSv) and 0.43 mSv (p < 0.005) for C-CT. The sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of the REDUCTION protocol to detect fractures were 0.98, 0.89, 0.98 and 0.89 respectively when two occult fractures were excluded. Inter- and intra-observer reliability for diagnosis using the REDUCTION protocol (kappa = 0.75, kappa = 0.71) were similar to those of C-CT (kappa = 0.85, kappa = 0.82). Using the REDUCTION protocol, 3D CT reconstructions were equivalent in quality and diagnostic information to those generated by C-CT (kappa = 0.87, kappa = 0.94). CONCLUSION: With a near 14-fold reduction in estimated ED compared with C-CT, the REDUCTION protocol reduces the amount of CT radiation substantially without significant diagnostic decay. It produces images that appear to be comparable with those of C-CT for evaluating fractures of the limbs. Cite this article: Bone Joint J 2016;98-B:1668-73.

The assessment, diagnosis, and management of fractures, particularly fractures that exhibit delayed healing, present considerable unique challenges to both patients and physicians. Fracture healing results from a complex series of biochemical events that may produce complete restoration of the anatomic and biochemical properties of the original osseous tissue. Fracture healing requires appropriate reduction, mechanical stability, and adequate vascularity to the fracture site; compromise of one of these elements may lead to delayed healing or nonunion. The patient's history, physical examination, and findings based on radiographs or other imaging modalities allow for assessment and characterization of the progression of healing. If nonunion is recognized, it is important for the clinician to understand the current treatment options that are available to optimize healing. Physical stimulation therapies include electromagnetic stimulation and low-intensity pulsed ultrasonography. Osteogenic factors used locally to promote fracture healing include autologous bone marrow and peptide signaling molecules such as platelet-derived growth factors, fibroblast growth factors, and bone morphogenetic proteins. Systemic biological protein such as parathyroid hormone and factors that target the Wnt family of signaling molecules offers promising data regarding its abilities to promote healing. Large segmental defects must be managed depending on the type and severity of the injury and may require treatment with bone grafts, induced membrane techniques, acute shortening, or distraction osteogenesis. A systematic approach in evaluating fracture union and an understanding of the modern methods to promote fracture healing will allow clinicians to significantly improve the treatment of patients with these injuries.

Mechanical loading is a potent anabolic regulator of bone mass, and the first line of defense for bone loss is weight-bearing exercise. Likewise, protected weight bearing is the first prescribed physical therapy following orthopedic reconstructive surgery. In both cases, enhancement of new bone formation is the goal. Our understanding of the physical cues, mechanisms of force sensation, and the subsequent cellular response will help identify novel physical and therapeutic treatments for age- and disuse-related bone loss, delayed- and nonunion fractures, and significant bony defects. This review highlights important new insights into the principles and mechanisms governing mechanical adaptation of the skeleton during homeostasis and repair and ends with a summary of clinical implications stemming from our current understanding of how bone adapts to biophysical force.

Reduced limb length discrepancy and more accurate cup positioning are purported benefits of using fluoroscopy for total hip arthroplasty (THA). The authors compared limb length discrepancy and cup position in 200 patients (group I, posterior approach without fluoroscopy; group II, anterior supine approach with fluoroscopy) who underwent primary THA. Mean limb length discrepancy was 2.7 mm (SD, 5.2 mm; range, -9.8 to 20.9 mm) and 0.7 mm (SD, 3.7 mm; range, -11.8 to 10.5 mm) for groups I and II, respectively (P=.002). In group I, 7% of hips had limb length discrepancy greater than 1 cm compared with 3% in group II. Mean cup inclination measured 40.8 degrees (SD, 5.0 degrees ; range, 26.1 degrees -53.7 degrees ) in group I and 43.4 degrees (SD, 5.6 degrees ; range, 31.3 degrees -55.9 degrees ) in group II (P=.008). In group I, 96% of cups had inclination within 10 degrees of the mean compared with 92% in group II (P=.24). Mean anteversion measured 35.3 degrees (SD, 7.1 degrees ; range, 17.8 degrees -60.7 degrees ) in group I and 25.9 degrees (SD, 8.2 degrees ; range, 1.5 degrees -44.8 degrees ) in group II (P=.0001). In group I, 87% of hips exhibited anteversion within 10 degrees of the mean compared with 76% in group II (P=.045). Although the anterior approach with intraoperative fluoroscopy reduced mean limb length discrepancy, the clinical significance of this reduction is unclear. Fluoroscopy reduced the incidence of limb length discrepancy greater than 1 cm. However, the use of fluoroscopy did not help to improve the precision of cup positioning. [Orthopedics. 2015; 38(5):e380-e386.].

Mechanical loading is a key anabolic regulator of bone mass. Stromal cell-derived factor-1 (SDF-1) is a stem cell homing factor that is important in hematopoiesis, angiogenesis, and fracture healing, though its involvement in skeletal mechanoadaptation is virtually unknown. The objective of this study was to characterize skeletal expression patterns of SDF-1 and CXCR4, the receptor for SDF-1, and to determine the role of SDF-1 signaling in load-induced periosteal bone formation. Sixteen-week-old C57BL/6 mice were treated with PBS or AMD3100, an antagonist against CXCR4, and exposed to in vivo ulnar loading (2.8 N peak-to-peak, 2 Hz, 120 cycles). SDF-1 was expressed in cortical and trabecular osteocytes and marrow cells, and CXCR4 was primarily expressed in marrow cells. SDF-1 and CXCR4 expression was enhanced in response to mechanical stimulation. The CXCR4 receptor antagonist AMD3100 significantly attenuated load-induced bone formation and led to smaller adaptive changes in cortical geometric properties as determined by histomorphometric analysis. Our data suggest that SDF-1/CXCR4 signaling plays a critical role in skeletal mechanoadaptation, and may represent a unique therapeutic target for prevention and treatment of age-related and disuse bone loss.