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Objective To examine whether components of metabolic syndrome (MetS), either singly or additively, were associated with the incidence of severe knee and hip OA, and whether these associations were independent of obesity assessed by body mass index (BMI). Methods Twenty thousand, four hundred and thirty participants who had blood lipids, anthropometric and blood pressure measurements during 2003–2007 were selected from the Melbourne Collaborative Cohort Study. MetS was defined as central obesity assessed by waist circumference and any two of raised triglyceride level, reduced HDL cholesterol level, hypertension or impaired fasting glycaemia. The incidence of total knee and hip replacement was determined by linking cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. Results Six hundred and sixty participants had knee OA and 562 had hip OA. After adjustment for age, gender, country of birth, education, physical activity and BMI, central obesity [hazard ratio (HR) 1.59, 95% confidence interval (CI) 1.25–2.01] and hypertension (1.24, 1.05–1.48) were associated with increased risk of knee OA. The accumulation of MetS components was associated with knee OA risk, independent of BMI: one component, 2.12 (1.15–3.91); two components, 2.92 (1.60–5.33) and three or more components, 3.09 (1.68–5.69). No statistically significant associations were observed for hip OA. Conclusion Cumulative number of MetS components and central obesity and hypertension were associated with increased risk of severe knee OA, independent of BMI. No associations were observed with severe hip OA. These findings suggest that the pathogenesis of knee and hip OA differ and that targeting the management of MetS may reduce the risk of knee OA.

Human osteoblast-like cells can be readily cultured from explants of trabecular bone, reproducibly expressing the characteristics of cells belonging to the osteoblastic lineage. Dual-color fluorescence-activated cell sorting was employed to develop a model of bone cell development in primary cultures of normal human bone cells (NHBCs) based on the cell surface expression of the stromal precursor cell marker STRO-1 and the osteoblastic marker alkaline phosphatase (ALP). Cells expressing the STRO-1 antigen exclusively (STRO-1+/ALP-), were found to exhibit qualities preosteoblastic in nature both functionally by their reduced ability to form a mineralized bone matrix over time, as measured by calcium release assay, and in the lack of their expression of various bone-related markers including bone sialoprotein, osteopontin, and parathyroid hormone receptor based on reverse trancriptase polymerase chain reaction (PCR) analysis. The majority of the NHBCs which expressed the STRO-1-/ALP+ and STRO-1-/ALP- phenotypes appeared to represent fully differentiated osteoblasts, while the STRO-1+/ALP+ subset represented an intermediate preosteoblastic stage of development. All STRO-1/ALP NHBC subsets were also found to express the DNA-binding transcription factor CBFA-1, confirming that these cultures represent committed osteogenic cells. In addition, our primer sets yielded four distinct alternative splice variants of the expected PCR product for CBFA-1 in each of the STRO-1/ALP subsets, with the exception of the proposed preosteoblastic STRO-1+/ALP- subpopulation. Furthermore, upon re-culture of the four different STRO-1/ALP subsets only the STRO-1+/ALP- subpopulation was able to give rise to all of the four subsets yielding the same proportions of STRO-1/ALP expression as in the original primary cultures. The data presented in this study demonstrate a hierarchy of bone cell development in vitro and facilitate the study of bone cell differentiation and function.

Bone loss is closely associated with many of the major causes of failure of total knee arthroplasty. It may cause loosening of the arthroplasty, fracture of an unsupported portion of the implant, or periprosthetic fracture. Severe bone loss can present a difficult reconstructive problem. Bone loss can be focal or widespread and occurs by various mechanisms. Adaptive bone remodeling can cause a diffuse loss of bone by stress shielding. Osteolysis can cause focal or diffuse defects at the bone prosthesis interface from a chronic inflammatory reaction to particulate debris. The acute inflammatory reaction associated with infection also can cause bone loss. Osteonecrosis is a rare reason for bone loss following total knee arthroplasty, where it may cause dramatic resorption of the patella. Bone loss is seen with all designs of total knee arthroplasty and with cemented or cementless fixation. Some factors, however, have been shown to exacerbate this phenomenon and it is important that these are recognized to minimize potential bone loss.

Background Increasing evidence suggests associations between osteoarthritis (OA) and the metabolic syndrome (MetS) and its components. Objectives The objective of this study was to examine whether components of MetS, either singly or additively, are associated with the incidence of severe knee and hip OA, and whether these associations were independent of obesity assessed by body mass index (BMI). Methods 21,837 participants who had fasting blood lipids, anthropometric and blood pressure measurements during 2003-2007 were selected from the Melbourne Collaborative Cohort Study. MetS was defined as central obesity assessed by waist circumference and any two of dyslipidaemia, hypertension or impaired fasting glycaemia (IGT). The incidence of severe OA requiring total knee and hip replacement was determined by linking the records to the Australian Orthopaedic Association National Joint Replacement Registry (AOA NJRR). Results 685 participants had knee OA and 580 had hip OA. After adjustment for age, gender, country of birth, education and BMI, central obesity (hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.20-1.91) and hypertension (1.25, 1.05-1.50) were associated with increased risk of knee OA. There was a dose-response relationship between the number of MetS components and knee OA risk, independent of BMI: one component 2.11 (1.11-4.01), two components 2.94 (1.57-5.52), three or more components 3.13 (1.66-5.91), p for trend Conclusions The cumulative number of MetS components and individual components of the MetS, central obesity and hypertension, are associated with increased risk of severe knee OA, independent of obesity. No association is seen for severe hip OA. The findings suggest different pathogenesis of knee and hip OA and that management of MetS may reduce the risk of knee OA. Disclosure of Interest None Declared

Introduction Racial and ethnic disparities in rates of total joint replacement have been described, but little work has been done in well-established migrant groups. The aim of this study was to compare the rates of primary joint replacement for osteoarthritis for Italian and Greek migrants to Australia and Australian-born individuals. Methods Eligible participants (n = 39,023) aged 27 to 75 years, born in Italy, Greece, Australia and the United Kingdom, were recruited for the Melbourne Collaborative Cohort Study between 1990 and 1994. Primary hip and knee replacement for osteoarthritis between 2001 and 2005 was determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry. Results Participants born in Italy and Greece had a lower rate of primary joint replacement compared with those born in Australia (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.26 to 0.39, P < 0.001), independent of age, gender, body mass index, education level, and physical functioning. This lower rate was observed for joint replacements performed in private hospitals (HR 0.17, 95% CI 0.13 to 0.23), but not for joint replacements performed in public hospitals (HR 0.96, 95% CI 0.72 to 1.29). Conclusions People born in Italy and Greece had a lower rate of primary joint replacement for osteoarthritis in this cohort study compared with Australian-born people, which could not simply be explained by factors such as education level, physical functioning, and weight. Although differential access to health care found in the population may explain the different rates of joint replacement, it may be that social factors and preferences regarding treatment or different rates of progression to end-stage osteoarthritis in this population are important to ethnic disparity.

Introduction Total joint replacement is considered a surrogate measure for symptomatic end-stage osteoarthritis. It is unknown whether the adipose mass and the distribution of adipose mass are associated with the risk of primary knee and hip replacement for osteoarthritis. The aim of the present investigation was to examine this in a cohort study. Methods A total of 39,023 healthy volunteers from Melbourne, Australia were recruited for a prospective cohort study during 1990 to 1994. Their body mass index, waist circumference, and waist-to-hip ratio were obtained from direct anthropometric measurements. The fat mass and percentage fat were estimated from bioelectrical impedance analysis. Primary knee and hip replacements for osteoarthritis between 1 January 2001 and 31 December 2005 were determined by data linkage to the Australian Orthopaedic Association National Joint Replacement Registry. Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) for primary joint replacement associated with each adiposity measure. Results Comparing the fourth quartile with the first, there was a threefold to fourfold increased risk of primary joint replacement associated with body weight (HR = 3.44, 95% confidence interval (CI) = 2.83 to 4.18), body mass index (HR = 3.44, 95% CI = 2.80 to 4.22), fat mass (HR = 3.51, 95% CI = 2.87 to 4.30), and percentage fat (HR = 2.99, 95% CI = 2.46 to 3.63). The waist circumference (HR = 2.77, 95% CI = 2.26 to 3.39) and waist-to-hip ratio (HR = 1.46, 95% CI = 1.21 to 1.76) were less strongly associated with the risk. Except for the waist-to-hip ratio, which was not significantly associated with hip replacement risk, all adiposity measures were associated with the risk of both knee and hip joint replacement, and were significantly stronger risk factors for knee. Conclusions Risk of primary knee and hip joint replacement for osteoarthritis relates to both adipose mass and central adiposity. This relationship suggests both biomechanical and metabolic mechanisms associated with adiposity contribute to the risk of joint replacement, with stronger evidence at the knee rather than the hip.

Summary Objectives There is ongoing debate regarding the optimal serum concentrations of 25-hydroxy-vitamin D for musculoskeletal health, including osteoarthritis (OA). The aim of this prospective cohort study was to determine whether serum 25-hydroxy-vitamin D concentrations were associated with the risk of hip arthroplasty for OA. Design This study examined 9135 participants from the Australian Diabetes, Obesity and Lifestyle Study who had serum 25-hydroxy-vitamin D measured in 1999–2000 and were aged ≥40 years at the commencement of arthroplasty data collection. The incidence of hip arthroplasty for OA during 2002–2011 was determined by linking cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. Results Over an average 9.1 (standard deviation (SD) 2.7) years of follow-up, 201 hip arthroplasties for OA were identified (males n = 90; females n = 111). In males, a one-standard-deviation increase in 25-hydroxy-vitamin D was associated with a 25% increased incidence (HR 1.25, 95% CI 1.02–1.56), with a dose response relationship evident by quartiles of 25-hydroxy-vitamin D concentration ( P for trend 0.04). These results were independent of age, body mass index (BMI), ethnicity, smoking status, physical activity, season of blood collection, latitude, hypertension and diabetes, area level disadvantage or after excluding those with extreme low 25-hydroxy-vitamin D concentrations. No significant association was observed in women (HR 1.10, 95% CI 0.87, 1.39). Conclusions Increasing serum 25-hydroxy-vitamin D concentrations were associated with an increased risk of hip arthroplasty for OA in males, while no significant association was observed in females. The mechanism for the association warrants further investigation.

Summary Objectives The role of the microcirculation in the pathogenesis of osteoarthritis (OA) remains unclear. This prospective cohort study examined the association between retinal vascular calibre and incidence of knee replacement for OA. Design 1838 participants of the Australian Diabetes, Obesity and Lifestyle (AusDiab) Study had retinal vascular calibre measured using a nonmydriatic digital fundus camera in 1999–2000 and were aged ≥40 years at joint replacement data collection commencement. The incidence of knee replacement for OA during 2002–2011 was determined by linking cohort records to the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). Results 77 participants underwent knee replacement for OA. They had narrower retinal arteriolar calibre compared with those without knee replacement (166.1 ± 24.8 μm vs 174.3 ± 24.5 μm, P = 0.004). For every one standard deviation reduction in retinal arteriolar calibre, the incidence of knee replacement increased by 25% (HR 1.25, 95% confidence interval (CI) 1.00–1.56). Participants in the narrower two-thirds of arteriolar calibre had twice the risk of knee replacement compared with those in the widest one-third (HR 2.00, 95% CI 1.07–3.74, P = 0.03) after adjustment for sex, body mass index (BMI), physical activity and HbA1c. There was no association for retinal venular calibre. Conclusions Retinal arteriolar narrowing is associated with increased risk of knee replacement for OA suggesting that further work is warranted to determine the role of the microcirculation in the pathogenesis of knee OA.

Chemotherapy is an established treatment modality for bone sarcomas such as osteosarcoma (OS). However, the use of chemotherapy in high-grade soft tissue sarcomas remains controversial, with the most active chemotherapeutic agent, doxorubicin (DOX), reported to have a response rate of, at best only 34% and most studies reporting lower response rates. Apo2L/TRAIL is a member of the tumour necrosis factor (TNF) family of cytokines and induces death of tumour cells, but not normal cells. Its potent apoptotic activity is mediated through cell surface death domain-containing receptors, DR4/TRAIL-R1 and DR5/TRAIL-R2. We investigated the efficacy of Apo2L/TRAIL as a single agent, and in combination with clinically relevant chemotherapeutic drugs, in fresh isolates of primary malignant cells obtained from biopsy material. The data presented here demonstrate that, in a range of primary bone related tumours, as well as soft tissue sarcomas, chemotherapeutic agents were only moderately effective, in terms of induction of cell death. Apo2L/TRAIL alone had little or no effect on any bone-related tumour or sarcoma in culture. In contrast, the combination of Apo2L/TRAIL and chemotherapeutic drugs produced a significant increase in tumour cell death, with DOX and Apo2L/TRAIL proving to be the most effective combination. These data suggest the potential for Apo2L/TRAIL to increase the effectiveness of chemotherapeutic drugs in bone and soft tissue sarcomas, while perhaps concurrently allowing a reduction in the exposure to drugs such as DOX, and a consequent reduction in toxicity. The synergistic action between these two different classes of agents has yet to be tested in vivo but may prove clinically relevant in the treatment of this refractive class of malignancies.

Objective Low birth weight (LBW) and preterm birth have been associated with adverse adult outcomes, including hypertension, insulin resistance, cardiovascular disease, and reduced bone mass. It is unknown whether LBW and preterm birth affect the risk of osteoarthritis (OA). This study aims to examine whether LBW and preterm birth were associated with the incidence of knee and hip arthroplasty for OA. Methods A total of 3,604 participants of the Australian Diabetes, Obesity and Lifestyle Study who reported their birth weight and history of preterm birth and were age >40 years at the commencement of arthroplasty data collection comprised the study sample. The incidence of knee and hip replacement for OA during 2002–2011 was determined by linking cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. Results One hundred and sixteen participants underwent knee arthroplasty and 75 underwent hip arthroplasty for OA. LBW (yes versus no; hazard ratio [HR] 2.04, 95% confidence interval [95% CI] 1.11–3.75, P = 0.02) and preterm birth (yes versus no; HR 2.50, 95% CI 1.29–4.87, P = 0.007) were associated with increased incidence of hip arthroplasty independent of age, sex, body mass index, education level, hypertension, diabetes mellitus, smoking, and physical activity. No significant association was observed for knee arthroplasty. Conclusion Although these findings will need to be confirmed, they suggest that individuals born with LBW or at preterm are at increased risk of hip arthroplasty for OA in adult life. The underlying mechanisms warrant further investigation.

Background The utilization of total hip replacement (THR) surgery is rapidly increasing, however few data examine whether these procedures are associated with socioeconomic status (SES) within Australia. This study examined primary THR across SES for both genders for the Barwon Statistical Division (BSD) of Victoria, Australia. Methods Using the Australian Orthopaedic Association National Joint Replacement Registry data for 2006–7, primary THR with a diagnosis of osteoarthritis (OA) among residents of the BSD was ascertained. The Index of Relative Socioeconomic Disadvantage was used to measure SES; determined by matching residential addresses with Australian Bureau of Statistics census data. The data were categorised into quintiles; quintile 1 indicating the most disadvantaged. Age- and sex-specific rates of primary THR per 1,000 person years were reported for 10-year age bands using the total population at risk. Results Females accounted for 46.9% of the 642 primary THR performed during 2006–7. THR utilization per 1,000 person years was 1.9 for males and 1.5 for females. The highest utilization of primary THR was observed in those aged 70–79 years (males 6.1, and females 5.4 per 1,000 person years). Overall, the U-shaped pattern of THR across SES gave the appearance of bimodality for both males and females, whereby rates were greater for both the most disadvantaged and least disadvantaged groups. Conclusions Further work on a larger scale is required to determine whether relationships between SES and THR utilization for the diagnosis of OA is attributable to lifestyle factors related to SES, or alternatively reflects geographic and health system biases. Identifying contributing factors associated with SES may enhance resource planning and enable more effective and focussed preventive strategies for hip OA.

Background: Pain is an indication for total hip arthroplasty (THA) and it should be resolved post-surgery. Because patients' pain is typically treated pharmacologically we tested whether opioid use can be used as a surrogate for patient-reported pain and as an indicator for early surgical failure. Specifically, we evaluated whether the amount of opioids taken within the year after THA was associated with one and five years risk of revision surgery. Methods: A cohort of 9943 THAs (01/2001-12/2012) was evaluated. Post-operative opioid use was the exposure of interest and cumulative daily oral morphine equivalent (OME) amounts were calculated. Total OMEs/90-day periods were categorised into quartiles. Revisions within one and five years were the outcomes of interest. Results: Of the THAs, 2.0 % (N = 200) were revised within one year and 4.2 % (N = 413) within five years. After adjustments for gender, age, surgical indication, co-morbidities, and other analgesics, revision was associated with amount of OMEs in the second quarter after THA (days 91-180 after discharge). Patients on medium-high amounts of OME (400-1119 mg) had higher risk of one (hazard ratio (HR) = 2.22, 95 % CI 1.08-4.56) and five year (HR = 1.66, 95 % CI 1.08-2.56) revision than a patient not taking opioids. During the same period, patients taking the highest amounts of OMEs (≥1120 mg) had a 2.64 (95 % CI 1.03-6.74) times higher risk of one year and a 2.11 (95 % CI 1.13-3.96) times higher risk of five year revision. Conclusions: Opioid use 91-180 days post-surgery is associated with higher risk of revision surgery and therefore is an early and useful indicator for surgical failure. Refereed/Peer-reviewed

Background Relatively little is known about the social distribution of total knee joint replacement (TKR) uptake in Australia. We examine associations between socioeconomic status (SES) and TKR performed for diagnosed osteoarthritis 2003–10 for all Australian males and females aged ≥30 yr. Methods Data of primary TKR (n = 213,018, 57.4% female) were ascertained from a comprehensive national joint replacement registry. Residential addresses were matched to Australian Census data to identify area-level social disadvantage, and categorised into deciles. Estimated TKR rates were calculated. Poisson regression was used to model the relative risk (RR) of age-adjusted TKR per 1,000py, stratified by sex and SES. Results A negative relationship was observed between TKR rates and SES deciles. Females had a greater rate of TKR than males. Surgery utilisation was greatest for all adults aged 70-79 yr. In that age group differences in estimated TKR per 1,000py between deciles were greater for 2010 than 2003 (females: 2010 RR 4.32 and 2003 RR 3.67; males: 2010 RR 2.04 and 2003 RR 1.78). Conclusions Identifying factors associated with TKR utilisation and SES may enhance resource planning and promote surgery utilisation for end-stage osteoarthritis. Electronic supplementary material The online version of this article (doi:10.1186/1471-2474-15-356) contains supplementary material, which is available to authorized users.

Y. Wang1, J.A. Simpson2, A.E. Wluka1, A.J. Teichtahl1, D.R. English2,3, G.G. Giles3, S. Graves4,5, F.M. Cicuttini1 1Dept. of Epidemiology and Preventive Med., Sch. of Publ. Hlth.and Preventive Med., Monash Univ., Melbourne, Australia; 2Ctr. for Molecular, Environmental, Genetic and Analytic Epidemiology, Sch. of Population Hlth., Univ. of Melbourne, Melbourne, Australia; 3Cancer Epidemiology Ctr., The Cancer Council Victoria, Melbourne, Australia; 4Dept. of Orthopaedic Surgery, Univ. of Melbourne, Royal Melbourne Hosp., Melbourne, Australia; 5AOA Natl. Joint Replacement Registry; Discipline of Publ. Hlth., Sch. of Population Hlth.& Clinical Practice, Univ. of Adelaide, Adelaide, Australia

were challenged by in vivo collagenase treatment, increased staining of the chondrocytes was seen. Conclusions: We identified a genetic variant on chromosome 19 to be associated with cartilage thickness and hip OA. The variant is located in a gene showing an expression pattern that supports a role in chondrogenetic differentiation. GWAS for underlying endophenotypes might be a prolific route to identify risk loci for complex diseases such as OA.