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Background: The definition of bone quality is evolving particularly from the perspective of anabolic agents that can enhance not only bone mineral density but also bone microarchitecture, composition, morphology, amount of microdamage, and remodeling dynamics.Questions/purposes: This review summarizes the molecular pathways and physiologic effects of current and potential anabolic drugs.Methods: From a MEDLINE search (1996-2010), articles were identified by the search terms "bone quality" (1851 articles), "anabolic agent" (5044 articles), "PTH or parathyroid hormone" (32,229 articles), "strontium" or "strontium ranelate" (283 articles), "prostaglandin" (77,539 articles), and "statin" or "statins" (14,233 articles). The search strategy included combining each with the phrase "bone quality." Another more limited search aimed at finding more novel potential agents.Results: Parathyroid hormone is the only US Food and Drug Administration-approved bone anabolic agent in the United States and has been the most extensively studied in in vitro animal and human trials. Strontium ranelate is approved in Europe but has not undergone Food and Drug Administration trials in the United States. All the studies on prostaglandin agonists have used in vivo animal models and there are no human trials examining prostaglandin agonist effects. The advantages of statins include the long-established advantages and safety profile, but they are limited by their bioavailability in bone. Other potential pathways include proline-rich tyrosine kinase 2 (PYK2) and sclerostin (SOST) inhibition, among others.Conclusions: The ongoing research to enhance the anabolic potential of current agents, identify new agents, and develop better delivery systems will greatly enhance the management of bone quality-related injuries and diseases in the future. [ABSTRACT FROM AUTHOR]

Background: Available options to fill fracture voids include autogenous bone, allograft bone, and synthetic bone materials. The objective of this meta-analysis was to determine whether the use of calcium phosphate bone cement improves clinical and radiographic outcomes and reduces fracture complications as compared with conventional treatment (with or without autogenous bone graft) for the treatment of fractures of the appendicular skeleton in adult patients.Methods: Multiple databases, online registers of randomized controlled trials, and the proceedings of the meetings of major national orthopaedic associations were searched. Published and unpublished randomized controlled trials were included, and data on methodological quality, population, intervention, and outcomes were abstracted in duplicate. Data were pooled across studies, and relative risks for categorical outcomes and weighted mean differences for continuous outcomes, weighted according to study sample size, were calculated. Heterogeneity across studies was determined, and sensitivity analyses were conducted.Results: We identified eleven published and three unpublished randomized controlled trials. Of the fourteen studies, six involved distal radial fractures, two involved femoral neck fractures, two involved intertrochanteric femoral fractures, two involved tibial plateau fractures, one involved calcaneal fractures, and one involved multiple types of metaphyseal fractures. All of the studies evaluated the use of calcium phosphate cement for the treatment of metaphyseal fractures occurring primarily through trabecular, cancellous bone. Autogenous bone graft was used in the control group in three studies, and no graft material was used in the remaining studies. Patients managed with calcium phosphate had a significantly lower prevalence of loss of fracture reduction in comparison with patients managed with autograft (relative risk reduction, 68%; 95% confidence interval, 29% to 86%) and had less pain at the fracture site in comparison with controls managed with no graft (relative risk reduction, 56%; 95% confidence interval, 14% to 77%). We were unable to compare pain at the bone-graft donor site between the studies because of methodological reasons. Three studies independently demonstrated improved functional outcomes when the use of calcium phosphate was compared with the use of no grafting material.Conclusions: The use of calcium phosphate bone cement for the treatment of fractures in adult patients is associated with a lower prevalence of pain at the fracture site in comparison with the rate in controls (patients managed with no graft material). Loss of fracture reduction is also decreased in comparison with that in patients managed with autogenous bone graft. [ABSTRACT FROM AUTHOR]

Over the past several years, there has been an increasing interest in the biology of bone repair and potential technologies for enhancing fracture-healing. Part of this interest is derived from the growing age of the population and the recognition that increased age carries an increased risk of complications after fracture. Although use of locally implanted or injected growth factors has received the most attention, systemic treatments for the enhancement of bone repair, especially for situations in which bone repair may be diminished or delayed, are now under investigation. Since the approval of parathyroid hormone (PTH) as an anabolic treatment for osteoporosis, there has been an increasing interest in other potential clinical uses for this compound in musculoskeletal conditions. It is now widely recognized that PTH administration is an effective therapy to increase bone mineral density and prevent fractures in patients with osteoporosis. More recently, a growing body of evidence has supported the conclusion that PTH will also be an effective anabolic therapy for the enhancement of bone repair after fracture. This review focuses on the recent research demonstrating the potential of PTH in the management of bone repair in a number of fracture models and also highlights the ongoing studies into the mechanisms of PTH actions on endochondral bone repair. [ABSTRACT FROM AUTHOR]

Background: The safety of simultaneous bilateral total knee replacement remains controversial. Some studies have demonstrated a higher rate of serious complications, including death, following bilateral procedures, whereas others have suggested no increase in the complication rate. The objective of this meta-analysis was to compare the safety of simultaneous bilateral total knee replacement with that of staged bilateral and unilateral total knee replacements.Methods: A computerized literature search was conducted to identify all citations, from 1966 to 2005, concerning bilateral total knee replacement. All of the English-language abstracts were obtained. A multistage assessment was then performed to identify articles fulfilling the inclusion criteria for the study. All randomized, prospective studies reporting the outcome of bilateral total knee replacement were included. The details of the reported data were extracted, and an extensive analysis of relevant variables was carried out.Results: One hundred and fifty published articles were identified, and eighteen that included a total of 27,807 patients (44,684 knees) were included in the meta-analysis. There were 10,930 unilateral total knee replacements, 16,419 simultaneous bilateral total knee replacements, and 458 staged bilateral total knee replacements with at least three months between the operative procedures. The prevalences of pulmonary embolism (odds ratio = 1.8), cardiac complications (odds ratio = 2.49), and mortality (odds ratio = 2.2) were higher after simultaneous bilateral total knee replacement. The prevalence of deep venous thrombosis was lower after simultaneous bilateral total knee replacement, but this difference was not significant. The complication rates after the staged bilateral total knee replacements were similar to those in the patients who had undergone unilateral total knee replacement only.Conclusions: Compared with staged bilateral or unilateral total knee replacement, simultaneous bilateral total knee replacement carries a higher risk of serious cardiac complications, pulmonary complications, and mortality. The period of time between staged procedures that would eliminate these increased risks could not be determined from this study.Level Of Evidence: Therapeutic Level III. [ABSTRACT FROM AUTHOR]

Bisphosphonates are the most clinically important class of antiresorptive agents available to treat diseases characterized by osteoclast-mediated bone resorption. Currently, seven bisphosphonates have the approval of the United States Food and Drug Administration. The most common adult diseases treated with bisphosphonates include osteoporosis, Paget disease, and metastatic bone disease. The treatment of pediatric disorders such as osteogenesis imperfecta and fibrous dysplasia with bisphosphonates has gained momentum, and initial investigations have demonstrated an acceptable safety profile. Currently, there is a lack of long-term follow-up data, which will be necessary for the development of responsible guidelines for therapy. [ABSTRACT FROM AUTHOR]

Background: Recombinant human parathyroid hormone (PTH [1-34]; teriparatide) is a new treatment for postmenopausal osteoporosis that can be systemically administered for the primary purpose of increasing bone formation. Because several studies have described the enhancement of fracture-healing and osteointegration in animals after use of PTH, we sought to critically analyze this skeletal effect.Methods: Two hundred and seventy male Sprague-Dawley rats underwent standard, closed femoral fractures and were divided into three groups that were administered daily subcutaneous injections of 5 or 30 mug/kg of PTH (1-34) or vehicle (control). The dosing was administered for up to thirty-five days. Groups were further divided into three subgroups and were killed on day 21, 35, or 84 after the fracture. The bones were subjected to mechanical torsion testing, histomorphometric analysis, or microquantitative computed tomography.Results: By day 21, calluses from the group treated with 30 mug of PTH showed significant increases over the controls with respect to torsional strength, stiffness, bone mineral content, bone mineral density, and cartilage volume. By day 35, both groups treated with PTH showed significant increases in bone mineral content and density and total osseous tissue volume, and they demonstrated significant decreases in void space and cartilage volume (p < 0.05). Torsional strength was significantly increased at this time-point in the group treated with 30 mug of PTH (p < 0.05). While dosing was discontinued on day 35, analyses performed after eighty-four days in the group treated with 30 mug of PTH showed sustained increases over the controls with respect to torsional strength and bone mineral density. No change was noted in osteoclast density at the time-points measured, suggesting that treatment with PTH enhanced bone formation but did not induce bone resorption.Conclusions: These data show that daily systemic administration of PTH (1-34) enhances fracture-healing by increasing bone mineral content and density and strength, and it produces a sustained anabolic effect throughout the remodeling phase of fracture-healing. [ABSTRACT FROM AUTHOR]

Background: Periprosthetic bone loss following total joint arthroplasty may threaten the survival of the implant. Bisphosphonates are effective in reducing bone loss in conditions associated with accelerated bone turnover. To determine the current understanding of the effect of bisphosphonates on periprosthetic bone mineral density after total joint arthroplasty, we conducted computerized searches for randomized controlled trials evaluating the use of bisphosphonates in patients treated with primary total joint arthroplasty.Methods: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, the web site of the United Kingdom National Research Register, and the archives of the American Academy of Orthopaedic Surgeons annual meetings (1989 through 2003), and we conducted hand searches of the bibliographies of relevant articles. We assessed methodological quality and abstracted relevant data. When necessary, we contacted authors to provide additional information.Results: Of 386 citations that were initially identified, six (five complete papers and one abstract), which included a total of 290 patients, met our inclusion criteria. Those papers showed that significantly less periprosthetic bone loss had occurred in the bisphosphonate-treated patients than in the control patients at three months (152 patients; weighted mean difference, 3.3%; 95% confidence interval, 1.9% to 4.7%; p < 0.01), six months (248 patients; weighted mean difference, 4.5%; 95% confidence interval, 1.6% to 7.4%; p < 0.001), and twelve months (197 patients; weighted mean difference, 4.2%; 95% confidence interval, 1.5% to 6.9%; p = 0.03). Bisphosphonates appeared to have a larger effect on bone loss following arthroplasties with cement than on bone loss following arthroplasties without cement (difference, 0.1%, 5%, and 5.4% at three, six, and twelve months; significant difference [p < 0.001] at one year only) and a larger effect on bone loss following total knee arthroplasties than on bone loss following total hip arthroplasties (difference, 4.1%, 11.5%, and 7.1% at three, six, and twelve months; significant difference [p < 0.001] at six months only). None of the studies related the effects of bisphosphonates on bone mineral density to clinically relevant outcomes.Conclusions: A meta-analysis of six randomized controlled trials suggested that bisphosphonates have a beneficial effect with regard to maintaining more periprosthetic bone mineral density than that in controls. However, the limitations of the available studies and the lack of analyses of clinically relevant outcomes (functional outcomes, revision rates, and quality of life) necessitate the planning and conduct of a sufficiently sized, methodologically sound study with clinically relevant end points. Until this has been done, the current evidence regarding the beneficial effects of bisphosphonates on periprosthetic bone after total joint arthroplasty should be interpreted with caution. [ABSTRACT FROM AUTHOR]

Purpose: Orthopaedic surgeons are frequently presented with advertisements for orthopaedic and medical products in which companies make claims of clinical and scientific fact. This study was designed to evaluate the statements made in orthopaedic print advertisements and determine whether they are supported by scientific data.Methods: Fifty statements from fifty advertisements were chosen at random from six peer-reviewed orthopaedic journals. The companies that placed the advertisements were contacted to provide supporting data for the statement of clinical or scientific fact. Three senior orthopaedic surgeons evaluated the data for quality and support. A high-quality study was defined as a study that could be published in the peer-reviewed literature. A well-supported statement was defined as a statement with enough supporting evidence to be used in clinical practice. The evaluating surgeons were blinded to product and company identification.Results: The supporting data were from a published source for eighteen claims (36%), from a presentation at a public forum or a scientific meeting for twelve claims (24%), or were "data on file" only at the company for twelve claims (24%). Interobserver agreement among the surgeons evaluating the advertisements for quality and support was good (the average intraclass correlation coefficient was 0.72). Of the fifty claims, twenty-two were considered unsupported by scientific data, seventeen were classified as possibly supported, seven were well supported, and four were from companies that did not respond despite three requests. Claims that were supported by published data were significantly more likely to be rated as well supported (p < 0.001). All twelve claims that were supported purely by "data on file" at the company were considered to be poorly supported.Conclusions: Orthopaedic surgeons should interpret claims made in orthopaedic print advertisements with caution. Approximately half of the claims are not supported by enough data to be used in a clinical decision-making process. [ABSTRACT FROM AUTHOR]

Background: Meniscal tears are frequently found during magnetic resonance imaging of osteoarthritic knees. However, the prevalence and clinical relevance of these tears have not been determined. This study was designed to investigate the relationship between meniscal tears and osteoarthritis and between such tears and pain in patients with osteoarthritis.Methods: Magnetic resonance imaging and plain radiography of the knee were performed in a group of 154 patients with clinical symptoms of knee osteoarthritis and a group of forty-nine age-matched asymptomatic controls. Pain scores (according to a 100-mm visual analog scale) and functional scores (according to the Western Ontario and McMaster University Osteoarthritis Index [WOMAC]) were determined for ninety-one of the patients with symptomatic osteoarthritis. Meniscal tears were defined as tears extending to an articular surface as seen on magnetic resonance imaging.Results: A medial or lateral meniscal tear was a very common finding in the asymptomatic subjects (prevalence, 76%) but was more common in the patients with symptomatic osteoarthritis (91%) (p < 0.005). In the group with symptomatic osteoarthritis, a higher Kellgren-Lawrence radiographic grade was correlated with a higher frequency of meniscal tears (r = 0.26, p < 0.001), and men had a higher prevalence of meniscal tears than did women (p < 0.01). However, there was no significant difference with regard to the pain or WOMAC score between the patients with and those without a medial or lateral meniscal tear in the osteoarthritic group (p = 0.8 to 0.9 for all comparisons). The power of the study was 80% to detect a difference in the WOMAC scores of 15 points and a difference in the scores on the visual analog scale of 16 mm.Conclusions: Meniscal tears are highly prevalent in both asymptomatic and clinically osteoarthritic knees of older individuals. However, osteoarthritic knees with a meniscal tear are not more painful than those without a tear, and the meniscal tears do not affect functional status. These data do not support the routine use of magnetic resonance imaging for the evaluation and management of meniscal tears in patients with osteoarthritis of the knee.Level Of Evidence: Diagnostic study, Level I-1 (testing of previously developed diagnostic criteria in series of consecutive patients [with universally applied reference "gold" standard]). See p. 2 for complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest form is provided with the online version of the article (http://links.lww.com/JBJSREV/B34).

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., Competing Interests: Disclosure This work was initially funded by PCORI. myarthritisrx.com, PCORI Tier III (3411628-003) award funding for Lifetime Initiative for the Management of Arthritis studies., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G729).

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., (© 2021 New York Academy of Sciences.)

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., (© 2019 New York Academy of Sciences.)

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., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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.)., (Copyright © 2019 Massachusetts Medical Society.)

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.

Economic evaluations are increasingly used to assess the value of health interventions, but variable quality and heterogeneity limit the use of these evaluations by decision-makers. These recommendations provide guidance for the design, conduct, and reporting of economic evaluations in osteoporosis to improve their transparency, comparability, and methodologic standards., Introduction: This paper aims to provide recommendations for the conduct of economic evaluations in osteoporosis in order to improve their transparency, comparability, and methodologic standards., Methods: A working group was convened by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis to make recommendations for the design, conduct, and reporting of economic evaluations in osteoporosis, to define an osteoporosis-specific reference case to serve a minimum standard for all economic analyses in osteoporosis, to discuss methodologic challenges and initiate a call for research. A literature review, a face-to-face meeting in New York City (including 11 experts), and a review/approval by a larger group of experts worldwide (including 23 experts in total) were conducted., Results: Recommendations on the type of economic evaluation, methods for economic evaluation, modeling aspects, base-case analysis and population, excess mortality, fracture costs and disutility, treatment characteristics, and model validation were provided. Recommendations for reporting economic evaluations in osteoporosis were also made and an osteoporosis-specific checklist was designed that includes items to report when performing an economic evaluation in osteoporosis. Further, 12 minimum criteria for economic evaluations in osteoporosis were identified and 12 methodologic challenges and need for further research were discussed., Conclusion: While the working group acknowledges challenges and the need for further research, these recommendations are intended to supplement general and national guidelines for economic evaluations, improve transparency, quality, and comparability of economic evaluations in osteoporosis, and maintain methodologic standards to increase their use by decision-makers.

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.

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Osteoarthritis (OA) is a leading cause of disability in the world. Mesenchymal stem cells (MSCs) have been studied to treat OA. This review was performed to systematically assess the quality of literature and compare the procedural specifics surrounding MSC therapy for osteoarthritis., Design: PubMed, CINAHL, EMBASE and Cochrane Central Register of Controlled Trials were searched for studies using MSCs for OA treatment (final search December 2017). Outcomes of interest included study evidence level, patient demographics, MSC protocol, treatment results and adverse events. Level I and II evidence articles were further analyzed., Results: Sixty-one of 3,172 articles were identified. These studies treated 2,390 patients with osteoarthritis. Most used adipose-derived stem cells (ADSCs) (n = 29) or bone marrow-derived stem cells (BMSCs) (n = 30) though the preparation varied within group. 57% of the sixty-one studies were level IV evidence, leaving five level I and nine level II studies containing 288 patients to be further analyzed. Eight studies used BMSCs, five ADSCs and one peripheral blood stem cells (PBSCs). The risk of bias in these studies showed five level I studies at low risk with seven level II at moderate and two at high risk., Conclusion: While studies support the notion that MSC therapy has a positive effect on OA patients, there is limited high quality evidence and long-term follow-up. The present study summarizes the specifics of high level evidence studies and identifies a lack of consistency, including a diversity of MSC preparations, and thus a lack of reproducibility amongst these articles' methods., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (Copyright © 2016 Bioventus LLC. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to characterize demographics, healing time, and complications of a large series of operatively treated atypical femur fractures., Design: Retrospective multicenter review., Setting: Seventeen academic medical centers., Patients: Bisphosphonate-related fractures as defined by American Society of Bone and Mineral Research. 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 body mass index 27.2. Average follow-up was 17 months. Twenty-one percent had a previous 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 before 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 TNFα. 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 TNFα/NF-κB signaling pathway and this is evidenced by the suppression of particle-induced IκB phosphorylation, NF-κB p65 nuclear translocation, and activity of the NF-κB-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.

Aims/hypothesis: Diabetes interferes with bone formation and impairs fracture healing, an important complication in humans and animal models. The aim of this study was to examine the impact of diabetes on mesenchymal stem cells (MSCs) during fracture repair., Methods: Fracture of the long bones was induced in a streptozotocin-induced type 1 diabetic mouse model with or without insulin or a specific TNFα inhibitor, pegsunercept. MSCs were detected with cluster designation-271 (also known as p75 neurotrophin receptor) or stem cell antigen-1 (Sca-1) antibodies in areas of new endochondral bone formation in the calluses. MSC apoptosis was measured by TUNEL assay and proliferation was measured by Ki67 antibody. In vitro apoptosis and proliferation were examined in C3H10T1/2 and human-bone-marrow-derived MSCs following transfection with FOXO1 small interfering (si)RNA., Results: Diabetes significantly increased TNFα levels and reduced MSC numbers in new bone area. MSC numbers were restored to normal levels with insulin or pegsunercept treatment. Inhibition of TNFα significantly reduced MSC loss by increasing MSC proliferation and decreasing MSC apoptosis in diabetic animals, but had no effect on MSCs in normoglycaemic animals. In vitro experiments established that TNFα alone was sufficient to induce apoptosis and inhibit proliferation of MSCs. Furthermore, silencing forkhead box protein O1 (FOXO1) prevented TNFα-induced MSC apoptosis and reduced proliferation by regulating apoptotic and cell cycle genes., Conclusions/interpretation: Diabetes-enhanced TNFα significantly reduced MSC numbers in new bone areas during fracture healing. Mechanistically, diabetes-enhanced TNFα reduced MSC proliferation and increased MSC apoptosis. Reducing the activity of TNFα in vivo may help to preserve endogenous MSCs and maximise regenerative potential in diabetic patients.

Introduction: Hip fractures are a leading cause of mortality and disability worldwide, and the number of hip fractures is expected to rise to over 6 million per year by 2050. The optimal approach for the surgical management of displaced femoral neck fractures remains unknown. Current evidence suggests the use of arthroplasty; however, there is lack of evidence regarding whether patients with displaced femoral neck fractures experience better outcomes with total hip arthroplasty (THA) or hemiarthroplasty (HA). The HEALTH trial compares outcomes following THA versus HA in patients 50 years of age or older with displaced femoral neck fractures., Methods and Analysis: HEALTH is a multicentre, randomised controlled trial where 1434 patients, 50 years of age or older, with displaced femoral neck fractures from international sites are randomised to receive either THA or HA. Exclusion criteria include associated major injuries of the lower extremity, hip infection(s) and a history of frank dementia. The primary outcome is unplanned secondary procedures and the secondary outcomes include functional outcomes, patient quality of life, mortality and hip-related complications-both within 2 years of the initial surgery. We are using minimisation to ensure balance between intervention groups for the following factors: age, prefracture living, prefracture functional status, American Society for Anesthesiologists (ASA) Class and centre number. Data analysts and the HEALTH Steering Committee are blinded to the surgical allocation throughout the trial. Outcome analysis will be performed using a χ(2) test (or Fisher's exact test) and Cox proportional hazards modelling estimate. All results will be presented with 95% CIs., Ethics and Dissemination: The HEALTH trial has received local and McMaster University Research Ethics Board (REB) approval (REB#: 06-151)., Results: Outcomes from the primary manuscript will be disseminated through publications in academic journals and presentations at relevant orthopaedic conferences. We will communicate trial results to all participating sites. Participating sites will communicate results with patients who have indicated an interest in knowing the results., Trial Registration Number: The HEALTH trial is registered with clinicaltrials.gov (NCT00556842)., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Fractures are the most common large-organ, traumatic injuries to humans. The repair of bone fractures is a postnatal regenerative process that recapitulates many of the ontological events of embryonic skeletal development. Although fracture repair usually restores the damaged skeletal organ to its pre-injury cellular composition, structure and biomechanical function, about 10% of fractures will not heal normally. This article reviews the developmental progression of fracture healing at the tissue, cellular and molecular levels. Innate and adaptive immune processes are discussed as a component of the injury response, as are environmental factors, such as the extent of injury to the bone and surrounding tissue, fixation and the contribution of vascular tissues. We also present strategies for fracture treatment that have been tested in animal models and in clinical trials or case series. The biophysical and biological basis of the molecular actions of various therapeutic approaches, including recombinant human bone morphogenetic proteins and parathyroid hormone therapy, are also discussed.