Sukhdeep Dulai

Bolus or weekly zoledronic acid administration does not delay endochondral fracture repair but weekly dosing enhances delays in hard callus remodeling

INTRODUCTION It has been widely assumed that osteoclasts play a pivotal role during the entire process of fracture healing. Bisphosphonates (BPs) are anti-catabolic agents commonly used to treat metabolic bone diseases including osteoporosis, minimizing fracture incidence. Yet, fractures do occur in these patients and the potential for negative effects of BPs on healing has been suggested. We aimed to examine the effect of different dosing regimes of the potent BP zoledronic acid (ZA) on early endochondral fracture repair and later callus remodeling in a normal bone healing environment. METHODS Saline, a Bolus dose of 0.1 degrees mg/kg ZA or 5 weekly divided doses of 0.02 degrees mg/kg of ZA commenced 1 week post operatively in a rat closed fracture model. Samples at 1, 2, 4 and 6 weeks post fracture were used to analyze initial fracture union, and 12 and 26 weeks post fracture to investigate the progress of remodeling. RESULTS ZA did not alter the rate of endochondral fracture union. All fractures united by 6 weeks, with no difference in the progressive reduction of cartilaginous soft callus between control and treatment groups over time. ZA treatment increased hard callus bone mineral content (BMC), volume and increased callus strength at 6 and 26 weeks post fracture. Hard callus remodeling commenced at 4 weeks post fracture with Bolus ZA treatment but was delayed until after 6 weeks in the Weekly ZA group. By 12 and 26 weeks, Bolus ZA had equivalent callus content of remodeled neo-cortical bone to the Saline controls, whereas Weekly ZA remained reduced compared to Saline controls at these times (P<0.01). Callus material properties such as peak stress were significantly reduced in both ZA groups at 6 weeks. At 26 weeks, Bolus ZA-treated calluses generated peak stress equivalent to control values, whereas Weekly ZA callus peak stress remained significantly reduced, indicating remodeling delay. CONCLUSIONS Osteoclast inhibition with ZA does not delay endochondral fracture repair in healthy rats. Bolus ZA treatment increased net callus size and strength at 6 weeks while allowing hard callus remodeling to proceed in the long term, albeit more slowly than control. Prolonged bisphosphonate dosing during repair does not delay endochondral ossification but can significantly affect remodeling long after the drug is ceased.

Decreased Bone Mineral Density in Neurofibromatosis Type 1: Results From a Pediatric Cohort

Neurofibromatosis type 1 (NF1) is a common genetic disorder affecting 1 in 3000 live births. It is well documented to be associated with bony deformities and other orthopaedic problems. Based on our observation that NF1 patients undergoing orthopaedic surgery often had osteopenic bone, we performed a study to assess the bone mineral density of a cohort of children with NF1 without orthopaedic defects. Twenty-three patients were recruited from the neurofibromatosis clinic. The bone mineral density of the total body, lumbar spine, and proximal femur was measured using dual-energy x-ray absorptiometry. Quantitative ultrasound was used to measure broadband ultrasonic attenuation at both heels. The groups mean dual-energy x-ray absorptiometry sex- and age-matched Z scores were below normal (−0.8 ± 1.1, −0.8 ± 1.2, −0.7 ± 0.8, −0.6 ± 1.1, −0.6 ± 0.9, −0.6 ± 1.1 for the total body, arms, legs, lumbar spine, and right and left femoral neck, respectively; all P < 0.01). Although some individuals had normal bone mass, 30% had total body Z scores below −1.5. The mean heel broadband ultrasonic attenuation Z score was also lower than normal (−0.8 ± 0.6; P < 0.001). Children with NF1 have a general tendency toward osteopenia, suggesting an abnormal underlying bone phenotype. This may be relevant when considering operative intervention and, if better understood, may partially explain poor bone healing associated with NF1.

A quality assessment of randomized clinical trials in pediatric orthopaedics.

The promotion and practice of evidence-based medicine necessitates a critical evaluation of medical literature, including the criterion standard of randomized clinical trials (RCTs). Recent studies have examined the quality of RCTs in various surgical specialties, but no study has focused on pediatric orthopaedics. The purpose of this study was to assess and describe the quality of RCTs published in the last 10 years in journals with high clinical impact in pediatric orthopaedics. All of the RCTs in pediatric orthopaedics published in 5 well-recognized journals between 1995 and 2005 were reviewed using the Detsky Quality Assessment Scale. The mean percentage score on the Detsky scale was 53% (95% confidence interval, 46%-60%). Only 7 (19%) of the articles satisfied the threshold for a satisfactory level of methodological quality (Detsky >75%). Most RCTs in pediatric orthopaedics that are published in well-recognized peer-reviewed journals demonstrate substantial deficiencies in methodological quality. Particular areas of weakness include inadequate rigor and reporting of randomization methods, use of inappropriate or poorly described outcome measures, inadequate description of inclusion and exclusion criteria, and inappropriate statistical analysis. Further efforts are necessary to improve the conduct and reporting of clinical trials in this field to avoid inadvertent misinformation of the clinical community.

Reproducibility of Acetabular Landmarks and a Standardized Coordinate System Obtained from 3D Hip Ultrasound

Two-dimensional (2D) ultrasound detection of developmental dysplasia of the hip (DDH) is limited by variation in acetabular appearance and alpha angle measurements, which change with position of the ultrasound probe. Three-dimensional (3D) ultrasound captures the entire acetabular shape, and a reproducible “standard central plane” may be generated, from two landmarks located on opposite ends of the acetabulum, for measurement of alpha angle and other indices. Two users identified landmarks on 51 3D ultrasounds, with ranging severity of disease, and inter- and intra-observer reproducibility of landmark and “standard plane” locations was compared; landmarks were chosen within 2 mm, and the “standard plane” rotation was reproducible within 10° between observers. We observed no difference in variability between alpha angles measured on the “standard plane” in comparison with 2D ultrasound. Applications of the standardized 3D ultrasound central plane will be to fuse serial ultrasounds for follow-up and development of new indices of 3D deformity.

The Quality of Randomized Controlled Trials in Pediatric Orthopaedics: Are We Improving?

Purpose: The quality of randomized controlled trials (RCTs) in orthopaedics is a topic of considerable importance, as RCTs play a major role in guiding clinical practice. The quality of RCTs published between 1995 and 2005 has previously been documented. The purpose of the current study was to assess and describe the quality of pediatric orthopaedic RCTs published from 2005 to 2012, by identifying study characteristics associated with higher quality and outlining areas for improvement. Methods: A standardized literature search was used to identify pediatric orthopaedic RCTs published in 7 well-recognized journals between September 2005 and July 2012 inclusive. The Detsky Quality Assessment Scale and the CONSORT checklist for Non-Pharmacologic Trials were used to assess the quality of the RCTs. Scores for the Detsky and CONSORT were calculated by 2 independent blinded orthopaedic surgeon reviewers with epidemiologic training. Results: Forty RCTs were included in this analysis. The mean percentage score on the Detsky quality scale was 67%. Sixteen (40%) of the articles satisfied the threshold for a satisfactory level of methodological quality (Detsky >75%). Twenty-five (63%) of these studies were negative studies, concluding no difference between treatment arms. In 52% of the negative studies, an a priori sample size analysis was absent, and 28% were self-described as underpowered. In multiple variable regression analysis, only working with a statistician was significantly associated with higher Detsky percentage scores (P=0.01). Conclusions: There is a trend for improving quality in pediatric orthopaedic RCTs. Compared with past reports, the mean Detsky score improved from 53% to 67%, and the proportion meeting an acceptable level of quality improved from 19% to 40%. One of the most concerning findings of this study was the lack of attention to sample size and power analysis, and the potential for underpowered studies. Ongoing efforts are necessary to improve the conduct and reporting of clinical trials in pediatric orthopaedics. Significance: Pediatric orthopaedic surgeons, JPO, and POSNA are working toward improving levels of quality in pediatric orthopaedic research. This paper highlights progress that has been made, and addresses some high-yield areas for future improvement.

Acute Pediatric Musculoskeletal Pain Management in North America A Practice Variation Survey

Children’s musculoskeletal (MSK) injury pain remains poorly managed. This survey of pediatric emergency physicians and orthopedic surgeons assessed analgesia administration practices and discharge advice for children with acute MSK pain; 683 responses were received. Ibuprofen was the most commonly reported analgesic used in the emergency department (52%) and at discharge (68%). Most (85%) reported using oral opioids in the previous 6 months. Codeine use was the most commonly reported opioid used in the emergency department (38%) and at home (51%). For equal levels of pain, younger children received less opioids than older children. Younger physicians and recent graduates chose acetaminophen and codeine more than older and more experienced colleagues, who preferred ibuprofen and non-codeine containing opioid compounds (P < .001 and .006, respectively). Orthopedic surgeons reported less ibuprofen use than pediatric emergency physicians (P < .001). Choice of analgesic agents is heterogeneous among physicians and is influenced by pain severity, child’s age, and physician characteristics.

Primary Wound Closure After Open Fracture: A Prospective Cohort Study Examining Nonunion and Deep Infection

Objectives: Determine the proportion of subjects developing deep infection or nonunion after primary wound closure of open fractures (humerus, radius/ulna, femur, and tibia/fibula). Secondarily, a matched-series analysis compared outcomes with subjects who underwent delayed wound closure. Design: Prospective cohort between 2009 and 2013 of subjects undergoing primary closure. Setting: Trauma center. Participants: Eighty-three (84 fractures) subjects were enrolled. Eighty-two (99%) subjects (83 fractures) provided follow-up data. Matching (age, sec, fracture location, and grade) was performed using study data of delayed wound closure undertaken at the same center between 2001 and 2009 (n = 68 matched subjects). Intervention: Primary wound closure occurred when the fracture grade was Gustilo grade 3A or lower and the wound deemed clean at initial surgery. Standardized evaluations occurred until the fracture(s) healed; phone interviews and chart reviews were also undertaken at 1 year. Main Outcome Measurements: Deep infection is defined as infection requiring unplanned surgical debridement and/or sustained antibiotic therapy after wound closure; nonunion is defined as unplanned surgical intervention after definitive wound closure or incomplete radiographic healing 1-year after fracture. Results: Three (4%) subjects had deep infections, whereas 10 (12%) subjects developed nonunion in the primary closure cohort. In the matched analyses [n = 68 pairs; (136 subjects)], the primary closure cohort had fewer deep infections [n = 3 (4%) vs. n = 6 (9%)] and nonunions [n = 9 (13%) vs. n = 19 (29%)] than the delayed closure cohort (P < 0.001). Conclusions: Primary wound closure after an open fracture appears acceptable in appropriately selected patients and may reduce the risk of deep infection and nonunion compared with delayed closure; a definitive randomized trial is needed. Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

An index for diagnosing infant hip dysplasia using 3-D ultrasound: the acetabular contact angle

BackgroundDevelopmental dysplasia of the hip (DDH) is a common condition that is highly treatable in infancy but can lead to the lifelong morbidity of premature osteoarthritis if left untreated. Current diagnostic methods lack reliability, which may be improved by using 3-D ultrasound.ObjectiveConventional 2-D US assessment of DDH has limitations, including high inter-scan variability. We quantified DDH on 3-D US using the acetabular contact angle (ACA), a property of the 3-D acetabular shape. We assessed ACA reliability and diagnostic utility.Materials and methodsWe prospectively collected data from January 2013 to December 2014, including 114 hips in 85 children divided into three clinical diagnostic groups: (1) normal, (2) initially borderline but ultimately normal without treatment and (3) dysplastic requiring treatment. Using custom software, two observers each traced acetabula twice on two 3-D US scans of each hip, enabling automated generation of 3-D surface models and ACA calculation. We computed inter-observer and inter-scan variability of repeatability coefficients and generated receiver operating characteristic (ROC) curves.ResultsThe 3-D US acetabular contact angle was reproduced 95% of the time within 6° in the same scan and within 9° in different scans of the same hip, vs. 9° and 14° for the 2-D US alpha angle (P < 0.001). Areas under ROC curves for diagnosis of developmental dysplasia of the hip were 0.954 for ACA and 0.927 for alpha angle.ConclusionThe 3-D US ACA was significantly more reliable than 2-D US alpha angle, and the 3-D US measurement predicted the presence of DDH with slightly higher accuracy. The ACA therefore shows promising initial diagnostic utility. Our findings call for further study of 3-D US in the diagnosis and longer-term follow-up of infant hip dysplasia.

Ultrasound Quantification of Acetabular Rounding in Hip Dysplasia: Reliability and Correlation to Treatment Decisions in a Retrospective Study

Currently, acetabular rounding is only subjectively assessed on ultrasound for developmental dysplasia of the hip. We tested whether acetabular rounding can be quantified reliably and can distinguish between hips requiring and not requiring treatment. Consecutive infants (n = 90) suspected of having dysplasia of the hip, seen at a pediatric orthopedic clinic, were separated into four diagnostic categories (normal, borderline but resolved, treated by brace, treated surgically). Acetabular rounding was assessed by semi-quantitative grade (0 = nil, 1 = mild, 2 = moderate, 3 = severe) by three observers and by direct measurement of acetabular radius of curvature (AROC) by two observers. Inter-observer reliability of rounding grade was poor (κ = 0.30-0.37). AROC had an inter-observer intra-class correlation coefficient of 0.84 and coefficient of variation of 29%-34%. Mean AROC was significantly higher for hips requiring treatment than for those not requiring treatment (3.3 mm vs. 1.6 mm, p = 0.007). AROC reliably quantifies an observation currently being made subjectively by radiologists and surgeons, and may be useful as a supplementary ultrasound index of dysplasia of the hip in future prospective studies.

Developmental Hip Dysplasia Diagnosis at Three-dimensional US: A Multicenter Study

Purpose To validate accuracy of diagnosis of developmental dysplasia of the hip (DDH) from geometric properties of acetabular shape extracted from three-dimensional (3D) ultrasonography (US). Materials and Methods In this retrospective multi-institutional study, 3D US was added to conventional two-dimensional (2D) US of 1728 infants (mean age, 67 days; age range, 3-238 days) evaluated for DDH from January 2013 to December 2016. Clinical diagnosis after more than 6 months follow-up was normal (n = 1347), borderline (Graf IIa, later normalizing spontaneously; n = 140) or dysplastic (Graf IIb or higher, n = 241). Custom software accessible through the institutions research portal automatically calculated indexes including 3D posterior and anterior alpha angle and osculating circle radius from hip surface models generated with less than 1 minute of user input. Logistic regression predicted clinical diagnosis (normal = 0, dysplastic = 1) from 3D indexes (ie, age and sex). Output represented probability of hip dysplasia from 0 to 1 (output: >0.9, dysplastic; 0.11-0.89, borderline; <0.1, normal). Software can be accessed through the research portal. Results Area under the receiver operating characteristic curve was equivalently high for 3D US indexes and 2D US alpha angle (0.996 vs 0.987). Three-dimensional US helped to correctly categorize 97.5% (235 of 241) dysplastic and 99.4% (1339 of 1347) normal hips. No dysplastic hips were categorized as normal. Correct diagnosis was provided at initial 3D US scan in 69.3% (97 of 140) of the studies diagnosed as borderline at initial 2D US scans. Conclusion Automatically calculated 3D indexes of acetabular shape performed equivalently to high-quality 2D US scans at tertiary medical centers to help diagnose DDH. Three-dimensional US reduced the number of borderline studies requiring follow-up imaging by over two-thirds.