An evidence-based guide to the treatment of osteonecrosis of the femoral head.

Non-traumatic osteonecrosis of the femoral head is a potentially devastating condition, the prevalence of which is increasing. Many joint-preserving forms of treatment, both medical and surgical, have been developed in an attempt to slow or reverse its progression, as it usually affects young patients. However, it is important to evaluate the best evidence that is available for the many forms of treatment considering the variation in the demographics of the patients, the methodology and the outcomes in the studies that have been published, so that it can be used effectively. The purpose of this review, therefore, was to provide an up-to-date, evidence-based guide to the management, both non-operative and operative, of non-traumatic osteonecrosis of the femoral head. Cite this article: Bone Joint J 2017;99-B:1267-79.

Entropy rate estimates from mutual information.

We show how to estimate the Kolmogorov-Sinai entropy rate for chaotic systems using the mutual information function, easily obtainable from experimental time series. We state the conditions under which the relationship is exact, and explore the usefulness of the approach for both maps and flows. We also explore refinements of the method, and study its convergence properties as a function of time series length.

Of mice and men, periodic limb movements and iron: how the human genome informs the mouse genome.

The gene, BTBD9, was recently linked to restless legs syndrome, periodic limb movements and iron status in humans. In a homologous region in mouse, an area containing btbd9 was also identified as being related to iron homeostasis. This finding is important as iron status in brain has been implicated in restless legs syndrome.

Extraction and characterization of metallic wear debris from total joint arthroplasty.

Wear debris generated from total joint arthroplasty may elicit a granulomatous and inflammatory response and has also been implicated in the development of osteolysis. Technical difficulty in retrieval and isolation of wear material from tissues has hindered the study of their physicochemical properties. The purpose of this study was to retrieve and analyze metallic wear debris from periprosthetic tissue obtained during revision arthroplasty. Tissue from six osteoarthritic patients was obtained during revision arthroplasty. The tissue was minced and then heated in a sodium dodecyl sulfate solution. Undigested tissue was incubated sequentially with papain and pepsin solutions. Metallic wear debris retrieved from the digestion procedure was analyzed by scanning electron microscopy. Wear fragments were seen as irregularly shaped flakes, splinters and polyhedral structures ranging from 1 to 100 microns in size. These structures appeared to be free from non-metallic surface-adherent material. Energy dispersion spectroscopy verified the presence of cobalt, chrome and molybdenum which comprised the implant alloy. Fatigue lines were observed on the surface suggesting brittle wear. Our technique for isolating metallic fragments facilitates the retrieval and preparation of wear debris for analysis of physicochemical properties and how wear debris interacts with cellular elements in surrounding tissue.

Common genetic variation in a basal promoter element alters DDAH2 expression in endothelial cells.

Synthesis of the vasodilator nitric oxide (NO) can be inhibited by the endogenous methylarginines L-NMMA and ADMA. ADMA is elevated in a number of cardiovascular disorders in which NO availability is reduced. Elimination of ADMA from the body occurs primarily by enzymatic breakdown through the action of DDAH, of which two isoforms exist, DDAH1 and DDAH2. In this study we have identified a core promoter region of the DDAH2 gene, and transcription factor sites that play an important role in the regulation of DDAH2 expression. Using PCR-SSCP analysis we also identified six common polymorphisms. One of these polymorphisms (an insertion/deletion at position -871) within the core promoter element influenced basal transcription. The discovery of a functional polymorphism within the DDAH2 promoter suggests that there may be common, individual differences in the ability to metabolise ADMA in vivo, that in turn, might underlie susceptibility to cardiovascular disease.

Genetic and environmental determinants of plasma nitrogen oxides and risk of ischemic heart disease.

Endothelial dysfunction, caused in part by reduced NO bioavailability, is a feature of hypercholesterolemia, hypertension, smoking, and atherosclerosis. We examined whether cholesterol, blood pressure, smoking status, and polymorphisms in the endothelial NO synthase gene (NOS 3) influence NO production (as assessed by the plasma levels of nitrogen oxides, NO(x)) in middle-aged men. We also determined whether plasma NO(x) or NOS 3 genotype predicted the risk of is chemic heart disease (IHD). We studied 3052 men who were initially free of IHD and recruited from 9 UK primary care practices. Blood pressure, age, body mass index, serum cholesterol, and smoking status were assessed at baseline and annually over 8.1 years of follow-up, and all IHD events were recorded. DNA samples were screened for 4 NOS 3 gene polymorphisms: -786 T/C, -922 A/G, 894 G/T (which predicts a Glu(298)-->Asp amino acid substitution in the mature protein), and a 27-bp tandem repeat in intron 4 (eNOS4a/4b). NO(x) was measured in plasma samples obtained on entry in 1121 participants from North Mymms and Chesterfield general practices, together with an additional 571 recruits selected at random. Genotype frequencies were in Hardy-Weinberg equilibrium, and linkage disequilibrium was detected between all the NOS 3 polymorphismsstudied, with the strongest allelic association being detected between -922 A/G and -786 T/C polymorphisms in the gene promoter (Delta=0.90, P<0.001). Plasma NO(x) was lower in smokers than in nonsmokers in the North Mymms (10.8+/-4.5 versus 11.8+/-4.6 micromol/L, P=0.13), Chesterfield (8.4+/-3.6 versus 9.9+/-4.0 micromol/L, P=0.01), and random samples (10.7+/-5.1 versus 11.7+/-4.7 micromol/L, P=0.03). A weak but significant inverse relationship was detected between plasma NO(x) and serum cholesterol only in the North Mymms data set (r=-0.14, P=0.02). No relationship was detected between plasma NO(x) and any of the NOS 3 polymorphisms, nor was there any association between any NOS 3 polymorphism and risk of an IHD event in either smokers or nonsmokers. These data support the hypothesis that the endothelial dysfunction observed in the blood vessels of smokers is related to reduced NO bioactivity but indicate that NOS 3 genotype does not influence significantly the level of plasma NO(x) or the risk of IHD in this population sample of middle-aged British men.

Strut-autografting with and without osteogenic protein-1 : a preliminary study of a canine femoral head defect model.

BACKGROUND: Osteonecrosis of the femoral head frequently leads to collapse of the articular cartilage and to disabling osteoarthritis, which ultimately may necessitate joint arthroplasty. One treatment method that has had moderate success is the so-called trapdoor approach, which involves excavation of diseased (necrotic) bone followed by bone-grafting. Augmentation of this procedure with various growth and differentiation factors may improve the outcome. We developed a canine model that mimics the clinical situation with trapdoor bone-grafting. The objective of this study was to evaluate the effect of the addition of osteogenic protein-1 on healing following the trapdoor procedure with strut-autografting. METHODS: Thirty-four skeletally mature dogs were used in the experiment. After capsulotomy, a trapdoor was created in the anterolateral surface of the femoral head and a 2-cm-diameter subchondral area of bone was removed. In the phase-I experiments, seven dogs had no treatment of the defect (Group I) and nine dogs were treated with strut-grafting (Group II). In phase II, the procedure was modified by collapsing the trapdoor into the created defect intraoperatively in eighteen dogs, which were divided into three equal groups: six untreated defects were left collapsed (Group III), six were treated with bone graft (Group IV), and six were treated with bone graft augmented with osteogenic protein-1 (Group V). RESULTS: Three of the seven femoral heads in Group I (untreated defect) and one of the nine heads in Group II (grafting without collapsing of the trapdoor) had evidence of cartilage collapse. Inspection of sagittal slices and radiographs revealed an unfilled residual defect in all Group-I heads, whereas all Group-II heads were well healed. The mean normalized stiffness value was significantly larger in Group II than it was in Group I. On visual inspection, depression was noted in all of the femoral heads in Group III (untreated defect; trapdoor left collapsed). In both Group IV and Group V (grafting without and with osteogenic protein-1), the trapdoor cartilage appeared to be essentially normal. Groups IV and V had more radiographic healing than did Group III. The defects in Group V (grafting with osteogenic protein-1) healed faster radiographically than did those in Group IV (grafting without osteogenic protein-1). CONCLUSIONS: Moderate-to-excellent healing was seen both radiographically and biomechanically by four months in the groups treated with grafting, with and without osteogenic protein-1, whereas untreated defects did not heal. CLINICAL RELEVANCE: Symptomatic osteonecrosis of the femoral head is a clinical challenge. The animal model in the current study is a useful tool for the evaluation of methods to treat osteonecrosis of the femoral head. Studies investigating additional time-periods between implantation of osteogenic protein-1 and assessment of results as well as different doses of osteogenic protein-1 are warranted.

Effect of PMMA particles and movement on an implant interface in a canine model.

The pathogenesis of aseptic loosening of total joint prostheses is not clearly understood. Two features are associated with loosened prostheses, namely, particulate debris and movement of the implant. While numerous studies have evaluated the cellular response to particulate biomaterials, few have investigated the influence of movement of the implant on the biological response to particles. Our aim was therefore to test the hypothesis that excessive mechanical stimulation of the periprosthetic tissues induces an inflammatory response and that the addition of particulate biomaterials intensifies this. We allocated 66 adult Beagle dogs to four groups as follows: stable implants with (I) and without (II) particulate polymethylmethacrylate (PMMA) and moving implants with (III) and without (IV) particulate PMMA. They were then evaluated at 2, 4, 6, 12 and 24 weeks. The stable implants were well tolerated and a thin, fibrous membrane of connective tissue was observed. There was evidence of positive staining in some cells for interleukin-6 (IL-6). Addition of particulate PMMA around the stable implants resulted in an increase in the fibroblastic response and positive staining for IL-6 and tumour necrosis factor-alpha (TNF-alpha). By contrast, movement of the implant resulted in an immediate inflammatory response characterised by large numbers of histiocytes and cytokine staining for IL-1beta, TNF-alpha and IL-6. Introduction of particulate PMMA aggravated this response. Animals with particulate PMMA and movement of the implant have an intense inflammatory response associated with accelerated bone loss. Our results indicate that the initiation of the inflammatory response to biomaterial particles was much slower than that to gross mechanical instability. Furthermore, when there was both particulate debris and movement, there was an amplification of the adverse tissue response as evidenced by the presence of osteolysis and increases in the presence of inflammatory cells and their associated cytokines.

Dioxin-inducible transactivation in a chromosomal setting. Analysis of the acidic domain of the Ah receptor.

We analyzed the transactivation function of the acidic segment of the Ah receptor (amino acids 515-583) by reconstituting AhR-defective mouse hepatoma cells with mutants. Our data reveal that both hydrophobic and acidic residues are important for transactivation and that these residues are clustered in two regions of the acidic segment of AhR. Both regions are crucial for function, because disruption of either one substantially impairs transactivation of the chromosomal CYP1A1 target gene. Neither region contains an amino acid motif that resembles those reported for other acidic activation domains. Furthermore, proline substitutions in both regions do not impair transactivation in vivo, a finding that implies that alpha-helix formation is not required for function.

Decreased insulin secretion in type 2 diabetes: a problem of cellular mass or function?

Type 2 diabetes is characterized by diminished or inappropriate secretion of insulin, which could be a defect of either islet cell function or beta-cell mass. Quantitation of islet cell populations in postmortem pancreas demonstrates little change of beta-cell mass in type 2 diabetes. Reduction of islet cell mass (up to 30%) is associated largely with islet amyloid deposition, and the degree of amyloidosis is independent of the duration of the disease. Insulin secretory capacity is dependent on both function and mass of cells. beta-Cell secretion is heterogeneous; increasing glucose concentrations result in recruitment of beta-cells into the secretory pool, indicating a large reserve of secretory capacity that can be recruited in insulin resistant conditions. The Starling curve of islet function describes the relationship of insulin secretion to increasing levels of insulin resistance and hyperglycemia in type 2 diabetes. Longitudinal studies in Macaca mulatta monkeys show that insulin resistance is accompanied by increased islet mass and onset of diabetes is associated with deposition of amyloid and reduction of beta-cells. Increasing the function of unresponsive beta-cells rather than the mass of cells may be a more effective therapeutic target for type 2 diabetes.

Human immunodeficiency virus testing for elective orthopedic procedures: results in a community-based hospital.

Between January 1, 1989 and July 31, 1995, voluntary preoperative screening tests for human immunodeficiency virus (HIV) infection, using an enzyme-linked immunosorbant assay, were completed on 2,727 patients who underwent elective orthopedic surgical procedures. There were 2,719 (99.7%) negative, 4 (0.15%) positive, and 3 (0.11%) false-positive results; 1 test was indeterminate (0.04%). All 4 positive patients were men with a mean age of 32 years (range: 26-43 years). Although the prevalence of positive tests is low in this setting, voluntary testing alerts the surgeon to higher risk patients, does not sacrifice patient care, and enables the incorporation of more extensive precautionary measures in the operating room to minimize occupational risks to the surgical team.

Total hip arthroplasty in patients receiving Workers' Compensation.

Numerous studies have reported on the adverse outcome of patients who sustain job-related injuries. In addition, studies have reported poor outcomes in patients receiving Workers' Compensation who undergo elective surgery. This study sought to determine the influence of Workers' Compensation on the outcome of patients who had undergone primary total hip arthroplasty. Between January 1984 and December 1996, 44 patients (48 hips) were studied. Of these, 17 were men and five were women with a mean age of 45 years (range, 27-76 years) at the time of surgery. These patients were receiving compensation benefits and were matched directly with a group of 22 patients who had 24 arthroplasties and were not receiving compensation. After a mean final followup of 77 months (range, 25-125 months), the compensation group had a mean Harris hip score of 86 points (range, 54-95 points). The matched control group had a mean Harris hip score of 92 points (range, 79-100 points) at a mean final duration of followup of 80 months. Two patients (9%) had undergone revision surgery for aseptic loosening at 28 and 67 months. The percentage of patients with good or excellent results did not differ significantly between the two groups. Based on these findings, the authors think that Workers' Compensation does not negatively influence the outcome of total hip arthroplasty.

Atraumatic osteonecrosis of the knee.

BACKGROUND: The purposes of this study were to define the clinical, demographic, and radiographic patterns of atraumatic osteonecrosis of the distal part of the femur and the proximal part of the tibia at presentation and to report the outcome of treatment of this condition. METHODS: Two hundred and forty-eight knees in 136 patients who were younger than the age of fifty-five years were treated at our institution between July 1, 1974, and September 15, 1998, for atraumatic osteonecrosis of the distal part of the femur or the proximal part of the tibia, or both. Demographic and radiographic features were characterized. The results of nonoperative treatment, core decompression, arthroscopic debridement, and total knee arthroplasty were evaluated. RESULTS: There were 106 female patients and thirty male patients, and their mean age was thirty-six years (range, fifteen to fifty-four years) at the time of diagnosis. One hundred and one patients (74 percent) had involvement of other large joints, with eighteen (13 percent) presenting initially with knee symptoms. One hundred and one patients (74 percent) had a disease that affected the immune system; sixty-seven of them had systemic lupus erythematosus. One hundred and twenty-three patients (90 percent) had a history of corticosteroid use. Technetium-99m bone-scanning missed lesions in sixteen (29 percent) of fifty-six knees. Eight (20 percent) of forty-one initially symptomatic knees treated nonoperatively had a successful clinical outcome (a Knee Society score of at least 80 points and no additional surgery) at a mean of eight years. The knees that remained severely symptomatic for three months were treated with either core decompression (ninety-one knees) or total knee arthroplasty (seven knees). Seventy-two (79 percent) of the ninety-one knees treated with core decompression had a good or excellent clinical outcome at a mean of seven years. Efforts to avoid total knee arthroplasty with repeat core decompression or arthroscopic debridement led to a successful outcome in fifteen (60 percent) of twenty-five knees. Thirty-four (71 percent) of forty-eight knees treated with total knee arthroplasty had a successful clinical outcome at a mean of nine years. CONCLUSIONS: Atraumatic osteonecrosis of the knee predominantly affects women, and in our study it was associated with corticosteroid use in 90 percent of the patients. Evaluation should include standard radiographic and magnetic resonance imaging of all symptomatic joints. Prognosis was negatively related to large juxta-articular lesions. Nonoperative treatment should be reserved for asymptomatic knees only. Core decompression was successful (a Knee Society score of at least 80 points and no additional surgery) in 79 percent of the knees in which the disease was in an early stage. Total knee arthroplasty was successful in only 71 percent of the knees.

Atraumatic osteonecrosis of the humeral head.

OBJECTIVE: To define the epidemiology, clinical and radiographic presentation, treatment, and prognosis of atraumatic osteonecrosis of the humeral head. METHODS: Of the 1,056 patients managed for osteonecrosis of any joint between July 1, 1974, and December 1, 1996, 127 shoulders in 73 patients were treated for atraumatic osteonecrosis of the proximal humerus. Clinical and radiographic characterization of this patient cohort was performed. RESULTS: At presentation, there were 47 women and 26 men with a mean age of 41 years (range 20-60). Numerous associated factors were noted: alcohol use (38%), moderate smoking (30%), asthma (8%), and nephrosis (3%). A corticosteroid association was noted in 60 patients (82%) and 42 of the patients (58%) had an immunocompromising disease. The severity of humeral head osteonecrosis did not correlate with dose or duration of corticosteroid therapy. According to the modified Ficat and Arlet radiographic staging system, there were 20 shoulders with Stage I disease, 55 shoulders with stage II disease, and 52 shoulders with Stage ITI or IV disease. Seventy-four of the shoulders treated with core decompression (78%) had good to excellent clinical outcomes at a mean followup of 6 years (range 2-21). Fourteen of the 16 patients (88%) treated with hemiarthroplasty or total shoulder arthroplasty were clinically successful at a mean followup 4 years (range 2-11). CONCLUSION: We observed a low incidence of humeral head involvement in the osteonecrosis patient cohort (7% of all osteonecrosis patients), and a high incidence of corticosteroid use (82%). hip involvement (81%), and bilateral disease (74%). Osteonecrosis of the humeral head should be suspected in patients presenting with shoulder pain and a history of osteonecrosis in other joints. Hip screening for osteonecrosis is advocated in patients with shoulder involvement. Early detection of shoulder osteonecrosis may permit a more conservative, joint-sparing approach as an alternative to surgical management.

Atraumatic osteonecrosis of the adult elbow.

Osteonecrosis is a disease that leads to joint destruction and often involves large joints, such as the hips, knees, and shoulders. Nontraumatic osteonecrosis of the adult elbow, to the best of the authors' knowledge, has not been reported. Nine adult patients with atraumatic osteonecrosis of 11 elbows were identified. The mean age at presentation was 36 years (range, 26-63 years); five patients were women and four were men. Six elbows involved the capitellum, three involved the lateral epicondyles, one involved the trochlea and radial head, and one involved medial and lateral epicondylar disease. All patients were receiving corticosteroid therapy, and no relationship between the duration or the amount of corticosteroid use and the severity of the osteonecrosis was found. Seven patients with radiographic Stage I and Stage II disease responded well to nonoperative treatments consisting of activity modification, analgesics, and a brief period of immobilization. Nonoperative treatment failed in two patients with Stage III disease, and they had core decompressions for pain relief. One patient with late Stage III disease in both elbows underwent bilateral total elbow arthroplasties. In contrast to the pediatric population, osteonecrosis of the adult elbow potentially can lead to end stage arthritis. If the osteonecrosis is diagnosed early, nonoperative treatment may be effective in relieving pain, although the long-term results of these treatments remain unknown.