Level of evidence trends in the Journal of Bone and Joint Surgery, 1980-2010.

INTRODUCTION: The Journal of Bone and Joint Surgery (JBJS-Am) began publishing the level of evidence (LOE) for manuscripts in 2003. From 1975 to 2005 JBJS-Am saw a trend towards higher leveled studies. We aimed to demonstrate trends in the country of origin of manuscripts published in JBJS-Am, and hypothesized that not only were more publications coming from groups outside of North America, but that the studies originating within North America were of higher LOE. METHODS: All articles published in The Journal of Bone and Joint Surgery (American) in 1980, 1985, 1990, 1995, 2000, 2005, and 2010 were independently evaluated by two reviewers and graded based on country, LOE (using the JBJS-Am LOE guidelines), and study type. For articles published after 2003 we used the level and study type published within the manuscript. RESULTS: The proportion of publications from North America decreased in 2005 and 2010 when compared to the previous 20 years (p>.03), but the overall number of publications appeared stable. Overall, there was an increase in Level I (r>.74, p>.03), Level II (r>.79, p>.02), and Level III (r>.95, p<.001) evidence studies. There was a statistically significant decrease in North American Level IV studies (r>-.81, p>.01) and an increase in international Level IV studies (r>.70, p>.04). International groups have increased therapeutic (r>.86, p<.01) and diagnostic studies (r>.93, p<.001). In North America and internationally, prognostic studies have not changed. North American groups have increased economic and decision analysis research (r>.69, p>.04). CONCLUSIONS: Over the past 30 years JBJS-Am has become more internationally diverse. International groups are publishing more therapeutic and diagnostic research than in the past, while North American groups have increased economic and decision analysis research. There has been a global effort towards higher leveled research.

Recommendations of the OARSI FDA Osteoarthritis Devices Working Group.

Osteoarthritis (OA) is the most common type of arthritis and a major cause of chronic musculoskeletal pain and functional disability. While both pharmacologic and non-pharmacologic modalities are recommended in the management of OA, when patients with hip or knee OA do not obtain adequate pain relief and/or functional improvement, joint replacement surgery or other surgical interventions should be considered. Total joint arthroplasties are reliable and cost-effective treatments for patients with significant OA of the hip and knee. Evidence from cohort and observational studies has confirmed substantial improvements in pain relief with cumulative revision rates at 10 years following total hip (THA) and total knee arthroplasties (TKA) at 7% and 10%, respectively. Joint replacements have been used in most every synovial joint, although results for joints other than hip and knee replacement have not been as successful. The evolution of new device designs and surgical techniques highlights the need to better understand the risk to benefit ratio for different joint replacements and to identify the appropriate methodology for evaluating the efficacy and optimal outcomes of these new devices, designed to treat OA joints.

Hip joint replacement surgery for idiopathic osteoarthritis aggregates in families.

In order to determine whether there is a genetic component to hip or knee joint failure due to idiopathic osteoarthritis (OA), we invited patients (probands) undergoing hip or knee arthroplasty for management of idiopathic OA to provide detailed family histories regarding the prevalence of idiopathic OA requiring joint replacement in their siblings. We also invited their spouses to provide detailed family histories about their siblings to serve as a control group. In the probands, we confirmed the diagnosis of idiopathic OA using American College of Rheumatology criteria. The cohorts included the siblings of 635 probands undergoing total hip replacement, the siblings of 486 probands undergoing total knee replacement, and the siblings of 787 spouses. We compared the prevalence of arthroplasty for idiopathic OA among the siblings of the probands with that among the siblings of the spouses, and we used logistic regression to identify independent risk factors for hip and knee arthroplasty in the siblings. Familial aggregation for hip arthroplasty, but not for knee arthroplasty, was observed after controlling for age and sex, suggesting a genetic contribution to end-stage hip OA but not to end-stage knee OA. We conclude that attempts to identify genes that predispose to idiopathic OA resulting in joint failure are more likely to be successful in patients with hip OA than in those with knee OA.

Hyaluronans in the treatment of osteoarthritis of the knee: evidence for disease-modifying activity.

OBJECTIVE: Although available nonsurgical pharmacotherapies for treatment of osteoarthritis (OA) are considered to be solely symptom-modifying agents, recent advances have been made in the search for agents that may modify disease progression. Intra-articular hyaluronan (HA) therapy is one symptom-modifying approach that has been found to be safe and effective for reducing pain due to OA of the knee. Presented here is a review of the evidence that HAs may also modify the rate of OA disease progression in addition to providing symptomatic efficacy. DESIGN: A review of the literature based on a MEDLINE search through June 2004, using the terms HA, sodium hyaluronate, hyaluronic acid, hylan, hylan G-F 20, OA, disease modification, structure modifying and joint structure. RESULTS: Evidence for disease-modifying activity of HAs stems from 1) the complex biochemical effects of HAs in the synovium and extracellular matrix of the articular cartilage, including interactions between exogenously administered HA and articular cartilage, subchondral bone, matrix proteoglycans, and collagens; 2) the effects of HA administration in animal models of OA, including total or partial meniscectomy and anterior cruciate ligament transectomy; 3) results of clinical trials using one HA, Hyalgan (sodium hyaluronate, molecular weight 500-730 kDa) that evaluated structural outcomes, such as joint-space width, chondrocyte density and vitality, and arthroscopic evaluation of chondropathy. DISCUSSION: Growing preclinical and clinical evidence supports the notion that, in addition to relieving the symptoms of OA, HAs also modify the structure of the diseased joint and the rate of OA disease progression, at least early in the evolution of the disease process.

Outcome of metal-backed cementless patellar components: the effect of implant design.

Failure of metal-backed cementless patellar components frequently has been observed clinically. To determine the effect of component design on clinical outcome, the authors reviewed the results of total knee arthroplasty with metal-backed patellar components of two different designs. The results of 168 total knee arthroplasties (Miller-Galante) with dome-shaped metal-backed patellar components and 93 total knee arthroplasties Miller-Galante II with modified dome-shaped metal-backed patellar components were reviewed. Kaplan-Meier survivorship was determined for both groups. Revision for patellar wear or failure was done or recommended in 36 Miller-Galante total knee arthroplasties. The cumulative survival rates at 3, 5, 7, and 9 years postoperatively were 99%, 92%, 81%, and 73%, respectively for this group. In contrast, only three of 93 Miller-Galante II patellar components required revision. Catastrophic patellar component failure, typically seen with the Miller-Galante metal-backed patellar components, was not observed with the Miller-Galante II components. Cumulative survival of the Miller-Galante II patella at 3, 5, 7, and 9 years postoperatively was 100%, 100%, 98.7%, and 93.2% respectively. The results of the current study show a dramatic reduction in metal-backed component failure by design changes incorporated into the modified dome-shaped Miller-Galante II patellar component and highlights the importance of design on the survival of cementless metal-backed patellar components.

Adherent endotoxin on orthopedic wear particles stimulates cytokine production and osteoclast differentiation.

Aseptic loosening of orthopedic implants is thought to be caused primarily by osteoclast differentiation induced by bone resorptive cytokines produced in response to phagocytosis of implant-derived wear particles. This study examined whether adherent endotoxin on the wear particles is responsible for inducing osteoclast differentiation as well as production of interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor a (TNF-alpha). Removal of adherent endotoxin almost completely inhibited the responses to titanium (Ti) particles by both murine marrow cells and human peripheral blood monocytes. In vivo experiments showed that endotoxin removal reduced particle-induced osteolysis by 50-70%. Addition of lipopolysaccharide (LPS) to the "endotoxin-free" particles restored their ability to induce cytokine production and osteoclast differentiation in vitro. Moreover, marrow cells from mice that are hyporesponsive to endotoxin because of mutation of Toll-like receptor 4 induced significantly less cytokine production and osteoclast differentiation in response to Ti particles with adherent endotoxin than did marrow cells from normoresponsive mice. This mutation also resulted in significantly less particle-induced osteolysis in vivo. Taken together, these results show that adherent endotoxin is involved in many of the biological responses induced by orthopedic wear particles and should stimulate development of new approaches designed to reduce the activity of adherent endotoxin in patients with orthopedic implants.

Cartilage regeneration using principles of tissue engineering.

It is well known that articular cartilage in adults has a limited ability for self-repair. Numerous methods have been devised to augment its natural healing response, but these methods generally lead to filling of the defect with fibrous tissue or fibrocartilage, which lacks the mechanical characteristics of articular cartilage and fails with time. Recently, tissue engineering has emerged as a new discipline that amalgamates aspects from biology, engineering, materials science, and surgery and that has as a goal the fabrication of functional new tissues to replace damaged tissues. The emergence of tissue engineering has facilitated the generation of new concepts and the revival of old ideas all of which has allowed a fresh approach to the repair or regeneration of tissues such as cartilage. The collaborations between scientists with different backgrounds and expertise has allowed the identification of some key principles that serve as the basis for the development of therapeutic approaches that now are less empiric and more hypothesis-driven than ever before. The current authors review some of the considerations regarding the various models used to test and validate the above repair methods and to address different aspects of the cartilage repair paradigm. Also, some key principles identified from past and current research, the need for the development of new biomaterials, and considerations in scale-up of cell-biomaterial constructs are summarized.

Tissue-engineered fabrication of an osteochondral composite graft using rat bone marrow-derived mesenchymal stem cells.

This study tested the tissue engineering hypothesis that construction of an osteochondral composite graft could be accomplished using multipotent progenitor cells and phenotype-specific biomaterials. Rat bone marrow-derived mesenchymal stem cells (MSCs) were culture-expanded and separately stimulated with transforming growth factor-beta1 (TGF-beta1) for chondrogenic differentiation or with an osteogenic supplement (OS). MSCs exposed to TGF-beta1 were loaded into a sponge composed of a hyaluronan derivative (HYAF-11) for the construction of the cartilage component of the composite graft, and MSCs exposed to OS were loaded into a porous calcium phosphate ceramic component for bone formation. Cell-loaded HYAFF-11 sponge and ceramic were joined together with fibrin sealant, Tisseel, to form a composite osteochondral graft, which was then implanted into a subcutaneous pocket in syngeneic rats. Specimens were harvested at 3 and 6 weeks after implantation, examined with histology for morphologic features, and stained immunohistochemically for type I, II, and X collagen. The two-component composite graft remained as an integrated unit after in vivo implantation and histologic processing. Fibrocartilage was observed in the sponge, and bone was detected in the ceramic component. Observations with polarized light indicated continuity of collagen fibers between the ceramic and HYAFF-11 components in the 6-week specimens. Type I collagen was identified in the neo-tissue in both sponge and ceramic, and type II collagen in the fibrocartilage, especially the pericellular matrix of cells in the sponge. These data suggest that the construction of a tissue-engineered composite osteochondral graft is possible with MSCs and different biomaterials and bioactive factors that support either chondrogenic or osteogenic differentiation.

Rapid repair of titanium particle-induced osteolysis is dramatically reduced in aged mice.

Aseptic loosening is the most common cause of orthopaedic implant failure. This process is thought to be due to osteolysis induced by implant-derived wear particles. Teitelbaum and colleagues have recently developed a promising murine calvarial model of wear particle-induced osteolysis. However, prior to this study, this model had only been assessed qualitatively. We now report a reproducible, quantitative version of the calvarial model of wear particle-induced osteolysis, in which the extent of osteolysis (and repair) of entire parietal bones is assessed by histomorphometry of contact microradiographs. Using this model, we found that the osteolytic response is transient and rapidly repaired in one month old mice. The extent of osteolysis peaks 7 days after particle implantation and returns to baseline levels by 13 days. A similar amount of osteolysis and even more extensive repair is observed when particles are implanted repeatedly. In contrast, aged mice develop progressive osteolysis with no detectable repair. As a result, 26 month old mice have approximately 17-fold more osteolysis than one month old mice 21 days after particle implantation. Skeletally mature, adult mice (4-16 months old) show an intermediate pattern of response. Osteolysis in these mice peaks at 7 days after particle implantation but it is repaired more slowly than in the one month old mice. Taken together, these results underscore the role of an imbalance between bone resorption and bone formation in the development of aseptic loosening and suggest that agents that stimulate bone formation maybe useful in prevention or treatment of aseptic loosening.

Titanium particles stimulate bone resorption by inducing differentiation of murine osteoclasts.

BACKGROUND: Loosening of orthopaedic implants is mediated by cytokines that elicit bone resorption and are produced in response to phagocytosis of implant-derived wear particles. This accelerated bone resorption could be due to increased osteoclastic activity, survival, or differentiation. Although a number of in vitro studies have shown that wear particles increase osteoclastic activity, the increase was less than twofold in all cases. The objective of the current study was to test the hypothesis that wear particles stimulate bone resorption by inducing osteoclast differentiation. METHODS: Conditioned media were prepared from murine marrow cells or human peripheral blood monocytes incubated in the presence or absence of titanium particles. The effects of conditioned media on osteoclast differentiation were examined with use of a recently developed assay in which osteoclast precursors are co-cultured with mesenchymal support cells. RESULTS: The present study showed that titanium particles induced both murine marrow cells and human peripheral blood monocytes to produce factors that stimulated osteoclast differentiation. The mean increase in osteoclast differentiation was 29.3+/-9.4-fold. The stimulation of osteoclast differentiation led to a parallel increase in bone resorption. The amount of stimulation was regulated in a dose-dependent manner by the concentration of both titanium particles and conditioned media. The stimulation of osteoclast differentiation required interactions between the cells and the particles themselves and, therefore, was not due to metal ions, soluble contaminants released from the particles, or submicrometer particles. In contrast, conditioned media from control cells incubated in the absence of titanium particles had no detectable effect on any of the examined parameters. CONCLUSIONS: The present study showed that titanium particles stimulate in vitro bone resorption primarily by inducing osteoclast differentiation. In contrast, the titanium particles had only small effects on osteoclast activity or survival.

BMP-2 induction and TGF-beta 1 modulation of rat periosteal cell chondrogenesis.

Periosteum contains osteochondral progenitor cells that can differentiate into osteoblasts and chondrocytes during normal bone growth and fracture healing. TGF-beta 1 and BMP-2 have been implicated in the regulation of the chondrogenic differentiation of these cells, but their roles are not fully defined. This study was undertaken to investigate the chondrogenic effects of TGF-beta 1 and BMP-2 on rat periosteum-derived cells during in vitro chondrogenesis in a three-dimensional aggregate culture. RT-PCR analyses for gene expression of cartilage-specific matrix proteins revealed that treatment with BMP-2 alone and combined treatment with TGF-beta 1 and BMP-2 induced time-dependent mRNA expression of aggrecan core protein and type II collagen. At later times in culture, the aggregates treated with BMP-2 exhibited expression of type X collagen and osteocalcin mRNA, which are markers of chondrocyte hypertrophy. Aggregates incubated with both TGF-beta 1 and BMP-2 showed no such expression. Treatment with TGF-beta 1 alone did not lead to the expression of type II or X collagen mRNA, indicating that this factor itself did not independently induce chondrogenesis in rat periosteal cells. These data were consistent with histological and immunohistochemical results. After 14 days in culture, BMP-2-treated aggregates consisted of many hypertrophic chondrocytes within a metachromatic matrix, which was immunoreactive with anti-type II and type X collagen antibodies. In contrast, at 14 days, TGF-beta 1 + BMP-2-treated aggregates did not contain any morphologically identifiable hypertrophic chondrocytes and their abundant extracellular matrix was not immunoreactive to the anti-type X collagen antibody. Expression of BMPR-IA, TGF-beta RI, and TGF-beta RII receptors was detected at all times in each culture condition, indicating that the distinct responses of aggregates to BMP-2, TGF-beta 1 and TGF-beta 1 + BMP-2 were not due to overt differences in receptor expression. Collectively, our results suggest that BMP-2 induces neochondrogenesis of rat periosteum-derived cells, and that TGF-beta 1 modulates the terminal differentiation in BMP-2 induced chondrogenesis.

Expression profile of protein tyrosine kinase genes in human osteoarthritis chondrocytes.

OBJECTIVE: To determine the expression profile of protein kinase (PK) and protein tyrosine kinase (PTK) genes in human primary osteoarthritis (OA) chondrocytes and to compare it with that of immortalized human chondrocytes T/C 28a4 with a view to learning whether T/C 28a4 cells can be used for elucidating signal transduction pathways in human chondrocytes. DESIGN: We used the Atlas Human cDNA Array and a method based on PCR with degenerate primers to analyse the expression profile of protein kinase genes in primary human OA chondrocytes and compared it with that of immortalized human chondrocyte cell line T/C 28a4 using RT-PCR and Western blotting. RESULTS: A total of 21 PTK genes were identified and several of these have never been shown to be expressed in human OA chondrocytes. Comparative expression analysis of some selected kinase genes showed that the mRNA expression pattern of many protein kinase genes in OA chondrocytes was identical to that of T/C 28a4 cells. However, there were differences in the level of protein expression of selected protein kinases in these cells. For example, mRNA expression of the novel kinase HCK was detected in OA chondrocytes and in the cell lines analysed but by Western blotting HCK protein was not detected in OA chondrocytes. In these studies, we also identified a novel mutant form of the discoidin domain receptor 2 (DDR2) transcript from chondrocyte-like cell line HTB-94. CONCLUSIONS: Our results provide novel information about protein kinase gene expression in OA chondrocytes and indicate that the transformed chondrocyte cell line T/C 28a4 may be suitable for elucidating signal transduction pathways in chondrocytes and to investigate how they regulate chondrocyte function in inflammatory and degenerative joint diseases.

Selection of bone grafts for revision total hip arthroplasty.

The selection of bone grafts to reconstruct deficient bone for revision hip replacement requires an understanding of specific bone graft functions and the critical steps of the biologic incorporation of the graft into the host. Bone grafts provide functions of osteogenesis, either graft derived or by osteoinduction, osteoconduction, or both, and mechanical support. Autologous cancellous bone provides excellent osteogenesis and osteoconduction without structural support. Nonvascularized cortical autografts provide mechanical support and are somewhat osteogenic. Allogeneic cancellous bone is osteoconductive and minimally osteoinductive, whereas cortical allografts provide structural support, if not freeze-dried, and are somewhat osteoconductive. Allogeneic demineralization bone matrix is highly osteoinductive. The selection of the appropriate bone graft depends on the classification of the bone deficiency. Cavitary (contained) defects can be reconstructed with cancellous morselized autograft, frozen or freeze-dried allograft, or allogeneic demineralized bone matrix. Segmental defects require bulk corticocancellous and/or cortical autografts or allografts. The ultimate incorporation of the bone graft depends on the interaction of the graft and the host's mechanical and biologic environment, and host-bone graft contact and stability. Optimum bone graft selection will enhance the clinical outcomes in revision total hip arthroplasty.

Hyaluronan-based polymers in the treatment of osteochondral defects.

Articular cartilage in adults has limited ability for self-repair. Some methods devised to augment the natural healing response stimulate some regeneration, but the repair is often incomplete and lacks durability. Hyaluronan-based polymers were tested for their ability to enhance the natural healing response. It is hypothesized that hyaluronan-based polymers recreate an embryonic-like milieu where host progenitor cells can regenerate the damaged articular surface and underlying bone. Osteochondral defects were made on the femoral condyles of 4-month-old rabbits and were left empty or filled with hyaluronan-based polymers. The polymers tested were ACP sponge, made of crosslinked hyaluronan, and HYAFF-11 sponge, made of benzylated hyaluronan. The rabbits were killed 4 and 12 weeks after surgery, and the condyles were processed for histology. All 12-week defects were scored with a 29-point scale, and the scores were compared with a Kruskall-Wallis analysis of variance on ranks. Untreated defects filled with bone tissue up to or beyond the tidemark, and the noncalcified surface layer varied from fibrous to hyaline-like tissue. Four weeks after surgery, defects treated with ACP exhibited bone filling to the level of the tidemark and the surface layer was composed of hyaline-like cartilage well integrated with the adjacent cartilage. At 12 weeks, the specimens had bone beyond the tidemark that was covered with a thin layer of hyaline cartilage. Four weeks after surgery, defects treated with HYAFF-11 contained a rim of chondrogenic cells at the interface of the implant and the host tissue. In general, the 12-week defects exhibited good bone fill and the surface was mainly hyaline cartilage. Treated defects received significantly higher scores than untreated defects (p < 0.05), and ACP-treated defects scored significantly higher than HYAFF-11-treated defects (p < 0.05). The introduction of these hyaluronan-based polymers into defects provides an appropriate scaffolding and favorable microenvironment for the reparative process. Further work is required to fully assess the long-term outcome of defects treated with these polymers.

Effect of resin type and manufacturing method on wear of polyethylene tibial components.

The purpose of this study was to examine the effect of ultrahigh molecular weight polyethylene resin type and manufacturing method on wear of Miller-Galante I and II tibial knee components. Thirteen Miller-Galante I and 10 Miller-Galante II components were retrieved at revision surgery. The Miller-Galante I tibial components were made by direct compression molding of Hi-fax 1900 resin and the Miller-Galante II tibial components were made by machining from ram extruded rod of GUR 415 resin. Both generations were gamma radiation sterilized in air. The Miller-Galante I retrievals had significantly more wear damage in the form of scratching and embedded metallic debris, whereas the Miller-Galante II retrievals had significantly more wear damage in the form of delamination. For the implants with an implantation time of 5 years or more, the Miller-Galante II polyethylene had a significantly greater maximum density value than did the Miller-Galante I polyethylene. Examination of thin sections of the Miller-Galante II components revealed that delamination occurred through a subsurface region of severely oxidatively degraded polyethylene; no such subsurface degraded region was observed for the Miller-Galante I components. The results of this study suggest that delamination of polyethylene tibial components that have been gamma radiation sterilized (in air) is influenced by resin type or manufacturing method or both.

Involvement of caspase-3 in epigallocatechin-3-gallate-mediated apoptosis of human chondrosarcoma cells.

Green tea polyphenol-(-)epigallocatechin-3-gallate (EGCG)-is a potent chemopreventive agent in many test systems and has been shown to inhibit tumor promotion and induce apoptosis. In this study we describe a novel observation that EGCG displayed strong inhibitory effects on the proliferation and viability of HTB-94 human chondrosarcoma cells in a dose-dependent manner and induced apoptosis. Investigation of the mechanism of EGCG-induced apoptosis revealed that treatment with EGCG resulted in DNA fragmentation, induction of caspase-3/CPP32 activity, and cleavage of the death substrate poly(ADP-ribose)polymerase (PARP). Pretreatment of cells with a synthetic pan-caspase inhibitor (Z-VAD-FMK) and a caspase-3-specific inhibitor (DEVD-CHO) prevented EGCG-induced PARP cleavage. The induction of apoptosis by EGCG via activation of caspase-3/CPP32-like proteases may provide a mechanistic explanation for its antitumor effects.