A Digital Platform for the Self-Management of Knee Arthritis: MyArthritisRx.com.

MyArthritisRx.com (MARx) is an online digital platform with resources to effectively manage osteoarthritis and directs patients to the appropriate information and tools to manage their disease. The key to self-management is a self-evaluation and staging program powered by an algorithm based on 150,000 arthritis patients. Outcome data (PROMs), comorbidities, demographics, and personalized characteristics are used to provide a personalized self-evaluation and staging assessment which characterizes disease severity and risk of progression. The initial 6-week program was completed by 100 pilot patients with 92% reporting some improvement. MARx offers evidence of efficacy with promise of cost savings and improved arthritis care.

Progranulin promotes bone fracture healing via TNFR pathways in mice with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) significantly increases bone fragility and fracture risk. Progranulin (PGRN) promotes bone fracture healing in both physiological and type 1 diabetic conditions. The present study aimed to investigate the role of PGRN in T2DM bone fracture healing. MKR mice (with an FVB/N genetic background) were used as the T2DM model. Drill-hole and Bonnarens and Einhorn models were used to investigate the role of PGRN in T2DM fracture healing in vivo. Primary bone marrow cells were isolated for molecular and signaling studies, and reverse transcription-polymerase chain reaction, immunohistochemical staining, and western blotting were performed to assess PGRN effects in vitro. PGRN mRNA and protein expression were upregulated in the T2DM model. Local administration of recombinant PGRN effectively promoted T2DM bone fracture healing in vivo. Additionally, PGRN could induce anabolic metabolism during endochondral ossification through the TNFR2-Akt and Erk1/2 pathways. Furthermore, PGRN showed anti-inflammatory activity in the T2DM bone regeneration process. These findings suggest that local administration of exogenous PGRN may be an alternative strategy to support bone regeneration in patients with T2DM. Additionally, PGRN might hold therapeutic potential for other TNFR-related metabolic disorders.

Principles of a 3D printed mechanical device for total knee balancing.

Implant alignment and soft-tissue balancing are important factors in total knee arthroplasty (TKA). The purpose of this study was to design a mechanical balancing device, which measures deflections resulting from forces applied on each condyle to provide numerical data indicating the extent of ligament release needed, or angular changes in the bone cuts required to achieve a balanced knee. Two mechanical devices were designed and 3D printed, Pistol Grip and In-line. The Pistol Grip design consisted of a lever system that indicated the difference between lateral and medial forces with a single pointer. The In-line design allows for the quantification of the absolute force applied on each individual condyle. The two designs were evaluated on a test rig designed to model balance and imbalance conditions in the knee. For the Pistol Grip design maximum pointer deflection indicates a 2 mm change in elevation per condyle and/or a 3 degrees angular change of the condyles which can be corrected by adjusting the ligament lengths equivalent to 2 mm and/or by modifying the proximal or distal femur bone cut by 3 degrees. For the In-line design, maximum pointer deflection represented a 40 N load on the condyle. Our mechanical balancer designs were successful in providing information that can guide surgeons to accurately achieve balance through ligamentous releases and/or modification to bone cuts. The balancer designs are easy to use, do not require any electronics or software, and can be incorporated into the surgical procedure.

Progranulin promotes diabetic fracture healing in mice with type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insulin deficiency, and patients with diabetes have an increased risk of bone fracture and significantly impaired fracture healing. Proinflammatory cytokine tumor necrosis factor-alpha is significantly upregulated in diabetic fractures and is believed to underlie delayed fracture healing commonly observed in diabetes. Our previous genetic screen for the binding partners of progranulin (PGRN), a growth factor-like molecule that induces chondrogenesis, led to the identification of tumor necrosis factor receptors (TNFRs) as the PGRN-binding receptors. In this study, we employed several in vivo models to ascertain whether PGRN has therapeutic effects in diabetic fracture healing. Here, we report that deletion of PGRN significantly delayed bone fracture healing and aggravated inflammation in the fracture models of mice with T1DM. In contrast, recombinant PGRN effectively promoted diabetic fracture healing by inhibiting inflammation and enhancing chondrogenesis. In addition, both TNFR1 proinflammatory and TNFR2 anti-inflammatory signaling pathways are involved in PGRN-stimulated diabetic fracture healing. Collectively, these findings illuminate a novel understanding concerning the role of PGRN in diabetic fracture healing and may have an application in the development of novel therapeutic intervention strategies for diabetic and other types of impaired fracture healing.

Inflammatory Profile and Osteogenic Potential of Fracture Haematoma in Humans.

Fracture haematoma forms immediately after fracture and is considered essential for the bone healing process. Its molecular composition has been briefly investigated with our current understanding being based on animal studies. This study aims to analyse the inflammatory cytokine content of fracture haematoma in humans and determine its effect on osteoprogenitor cells. Twenty-three patients were recruited following informed consent. Peripheral blood, fracture haematoma and bone were collected. A Luminex assay on the levels of 34 cytokines was performed and autologous peripheral blood samples served as control. Mesenchymal Stem Cells (MSCs) were isolated following collagenase digestion and functional assays were performed. Gene expression analysis of 84 key osteogenic molecules was performed. Thirty-three inflammatory cytokines were found to be significantly raised in fracture haematoma when compared to peripheral serum (p < 0.05). Amongst the most raised molecules were IL-8, IL-11 and MMP1, -2 and -3. Fracture haematoma did not significantly affect MSC proliferation, but ALP activity and calcium deposition were significantly increased in the MSCs undergoing osteogenic differentiation. Medium supplementations with fracture haematoma resulted in a statistically significant upregulation of osteogenic genes including the EGF, FGF2 and VEGFA. This seems to be the pathway involved in the osteogenic effect of fracture haematoma on bone cells. In conclusion, fracture haematoma is found to be a medium rich in inflammatory and immunomodulatory mediators. At the same time, it contains high levels of anti-inflammatory molecules, regulates osteoclastogenesis, induces angiogenesis and the production of the extracellular matrix. It appears that fracture haematoma does not affect osteoprogenitor cells proliferation as previously thought, but induces an osteogenic phenotype.

Total Hip Arthroplasty or Hemiarthroplasty for Hip Fracture.

BACKGROUND: Globally, hip fractures are among the top 10 causes of disability in adults. For displaced femoral neck fractures, there remains uncertainty regarding the effect of a total hip arthroplasty as compared with hemiarthroplasty. METHODS: We randomly assigned 1495 patients who were 50 years of age or older and had a displaced femoral neck fracture to undergo either total hip arthroplasty or hemiarthroplasty. All enrolled patients had been able to ambulate without the assistance of another person before the fracture occurred. The trial was conducted in 80 centers in 10 countries. The primary end point was a secondary hip procedure within 24 months of follow-up. Secondary end points included death, serious adverse events, hip-related complications, health-related quality of life, function, and overall health end points. RESULTS: The primary end point occurred in 57 of 718 patients (7.9%) who were randomly assigned to total hip arthroplasty and 60 of 723 patients (8.3%) who were randomly assigned to hemiarthroplasty (hazard ratio, 0.95; 95% confidence interval [CI], 0.64 to 1.40; P = 0.79). Hip instability or dislocation occurred in 34 patients (4.7%) assigned to total hip arthroplasty and 17 patients (2.4%) assigned to hemiarthroplasty (hazard ratio, 2.00; 99% CI, 0.97 to 4.09). Function, as measured with the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score, pain score, stiffness score, and function score, modestly favored total hip arthroplasty over hemiarthroplasty. Mortality was similar in the two treatment groups (14.3% among the patients assigned to total hip arthroplasty and 13.1% among those assigned to hemiarthroplasty, P = 0.48). Serious adverse events occurred in 300 patients (41.8%) assigned to total hip arthroplasty and in 265 patients (36.7%) assigned to hemiarthroplasty. CONCLUSIONS: Among independently ambulating patients with displaced femoral neck fractures, the incidence of secondary procedures did not differ significantly between patients who were randomly assigned to undergo total hip arthroplasty and those who were assigned to undergo hemiarthroplasty, and total hip arthroplasty provided a clinically unimportant improvement over hemiarthroplasty in function and quality of life over 24 months. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov number, NCT00556842.).

A Comparison of Treatment Effects for Nonsurgical Therapies and the Minimum Clinically Important Difference in Knee Osteoarthritis: A Systematic Review.

BACKGROUND: The minimum clinically important difference (MCID) was developed to ascertain the smallest change in an outcome that patients perceive as beneficial. The objectives of the present review were (1) to compare the MCIDs for pain assessments used among guidelines and meta-analyses investigating different nonsurgical therapies for knee osteoarthritis and (2) to compare the effect estimates of different nonsurgical interventions against a single commonly-utilized MCID threshold. METHODS: Systematic and manual searches were conducted to identify guidelines and meta-analyses evaluating pain outcomes for nonsurgical knee osteoarthritis interventions. Individual treatment effects for pain were presented on a common scale (the standardized mean difference [SMD]). To evaluate the perception of the relative benefit of each nonsurgical treatment, the variation in MCIDs selected from the published MCID literature was assessed. RESULTS: Thirty-seven guidelines and meta-analyses were included. MCIDs were often presented as an SMD or a mean difference (MD) on a validated scale and varied in magnitude across sources. This analysis demonstrated that intra-articular hyaluronic acid, intra-articular corticosteroids, and acetaminophen all had relatively larger effect sizes than topical nonsteroidal anti-inflammatory drugs (NSAIDs). Higher-molecular-weight intra-articular hyaluronic acid had a greater relative effect compared with both non-selective and cyclooxygenase-2-selective oral NSAIDs. Evaluating the treatment effect estimates against a commonly utilized MCID revealed similarities in which observations attained clinical significance among treatments; however, this observation varied across the range of reported MCIDs. CONCLUSIONS: The present review confirmed the variability in the MCIDs for pain assessments that are used across guidelines and meta-analyses evaluating nonsurgical interventions for knee osteoarthritis. This variability may yield conflicting treatment recommendations, ranging from rejecting treatments that are indeed efficacious to accepting treatments that may not be beneficial. Additional research is required to determine why some nonsurgical therapies are more consistently recommended in knee osteoarthritis guidelines than others as these findings suggest similarities in their effect estimates for pain. Relevant stakeholders need to reach a consensus on a standard approach to determining the MCIDs for these therapies to ensure that appropriate and effective treatment options are available to patients prior to invasive surgical intervention. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The Role of Patient Education in Arthritis Management: The Utility of Technology.

Technologies continue to shape the path of medical treatment. Orthopedic surgeons benefit from becoming more aware of how twenty-first century information technology (IT) can benefit patients. The percentage of orthopedic patients utilizing IT resources is increasing, and new IT tools are becoming utilized. These include disease-specific applications. This article highlights the opportunity for developing IT tools applicable to the growing population of patients with osteoarthritis (OA), and presents a potential solution that can facilitate the way OA education and treatment are delivered, and thereby maximize efficiency for the health care system, the physician, and the patient.

Orthobiologics A Comprehensive Review of the Current Evidence and Use in Orthopedic Subspecialties.

Orthobiologics are organic and synthetic materials that are used in and outside of the operating room to augment both bone and soft tissue healing. The orthobiologics portfolio has vastly expanded over the years, and it has become imperative for orthopedic surgeons to understand the role and function of this new class of biologic adjuvants. This review will highlight key components and product groups that may be relevant for the practicing orthopedic surgeon in any subspecialty. This by no means is an extensive list of the available products but provides an important overview of the most highlighted products available in the market today. Those discussed include, bone void fillers, extracelluar matrix (ECM) products, platelet-rich plasma (PRP), bone morphogenetic protein-2 (BMP-2), bone marrow aspirate (BMA), bone marrow aspirate concentrate (BMAC), and mesenchymal stem cells (MSCs). These are further categorized into their uses in several subspecialties including, traumatology, sports medicine, sports surgery, and spine surgery.

TNFα contributes to diabetes impaired angiogenesis in fracture healing.

Diabetes increases the likelihood of fracture, interferes with fracture healing and impairs angiogenesis. The latter may be significant due to the critical nature of angiogenesis in fracture healing. Although it is known that diabetes interferes with angiogenesis the mechanisms remain poorly defined. We examined fracture healing in normoglycemic and streptozotocin-induced diabetic mice and quantified the degree of angiogenesis with antibodies to three different vascular markers, CD34, CD31 and Factor VIII. The role of diabetes-enhanced inflammation was investigated by treatment of the TNFα-specific inhibitor, pegsunercept starting 10days after induction of fractures. Diabetes decreased both angiogenesis and VEGFA expression by chondrocytes. The reduced angiogenesis and VEGFA expression in diabetic fractures was rescued by specific inhibition of TNF in vivo. In addition, the TNF inhibitor rescued the negative effect of diabetes on endothelial cell proliferation and endothelial cell apoptosis. The effect of TNFα in vitro was enhanced by high glucose and an advanced glycation endproduct to impair microvascular endothelial cell proliferation and tube formation and to stimulate apoptosis. The effect of TNF, high glucose and an AGE was mediated by the transcription factor FOXO1, which increased expression of p21 and caspase-3. These studies indicate that inflammation plays a major role in diabetes-impaired angiogenesis in endochondral bone formation through its effect on microvascular endothelial cells and FOXO1.

Bone fracture nonunion rate decreases with increasing age: A prospective inception cohort study.

BACKGROUND: Fracture nonunion risk is related to severity of injury and type of treatment, yet fracture healing is not fully explained by these factors alone. We hypothesize that patient demographic factors assessable by the clinician at fracture presentation can predict nonunion. METHODS: A prospective cohort study design was used to examine ~2.5 million Medicare patients nationwide. Patients making fracture claims in the 5% Medicare Standard Analytic Files in 2011 were analyzed; continuous enrollment for 12months after fracture was required to capture the ICD-9-CM nonunion diagnosis code (733.82) or any procedure codes for nonunion repair. A stepwise regression analysis was used which dropped variables from analysis if they did not contribute sufficient explanatory power. In-sample predictive accuracy was assessed using a receiver operating characteristic (ROC) curve approach, and an out-of-sample comparison was drawn from the 2012 Medicare 5% SAF files. RESULTS: Overall, 47,437 Medicare patients had 56,492 fractures and 2.5% of fractures were nonunion. Patients with healed fracture (age 75.0±12.7SD) were older (p<0.0001) than patients with nonunion (age 69.2±13.4SD). The death rate among all Medicare beneficiaries was 4.8% per year, but fracture patients had an age- and sex-adjusted death rate of 11.0% (p<0.0001). Patients with fracture in 14 of 18 bones were significantly more likely to die within one year of fracture (p<0.0001). Stepwise regression yielded a predictive nonunion model with 26 significant explanatory variables (all, p≤0.003). Strength of this model was assessed using an area under the curve (AUC) calculation, and out-of-sample AUC=0.710. CONCLUSIONS: A logistic model predicted nonunion with reasonable accuracy (AUC=0.725). Within the Medicare population, nonunion patients were younger than patients who healed normally. Fracture was associated with increased risk of death within 1year of fracture (p<0.0001) in 14 different bones, confirming that geriatric fracture is a major public health issue. Comorbidities associated with increased risk of nonunion include past or current smoking, alcoholism, obesity or morbid obesity, osteoarthritis, rheumatoid arthritis, type II diabetes, and/or open fracture (all, multivariate p<0.001). Nonunion prediction requires knowledge of 26 patient variables but predictive accuracy is currently comparable to the Framingham cardiovascular risk prediction.

Re-evaluation of low intensity pulsed ultrasound in treatment of tibial fractures (TRUST): randomized clinical trial.

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.