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The Bone & Joint Journal
Vol. 106-B, Issue 11 | Pages 1333 - 1341
1 Nov 2024
Cheung PWH Leung JHM Lee VWY Cheung JPY

Aims. Developmental cervical spinal stenosis (DcSS) is a well-known predisposing factor for degenerative cervical myelopathy (DCM) but there is a lack of consensus on its definition. This study aims to define DcSS based on MRI, and its multilevel characteristics, to assess the prevalence of DcSS in the general population, and to evaluate the presence of DcSS in the prediction of developing DCM. Methods. This cross-sectional study analyzed MRI spine morphological parameters at C3 to C7 (including anteroposterior (AP) diameter of spinal canal, spinal cord, and vertebral body) from DCM patients (n = 95) and individuals recruited from the general population (n = 2,019). Level-specific median AP spinal canal diameter from DCM patients was used to screen for stenotic levels in the population-based cohort. An individual with multilevel (≥ 3 vertebral levels) AP canal diameter smaller than the DCM median values was considered as having DcSS. The most optimal cut-off canal diameter per level for DcSS was determined by receiver operating characteristic analyses, and multivariable logistic regression was performed for the prediction of developing DCM that required surgery. Results. A total of 2,114 individuals aged 64.6 years (SD 11.9) who underwent surgery from March 2009 to December 2016 were studied. The most optimal cut-off canal diameters for DcSS are: C3 < 12.9 mm, C4 < 11.8 mm, C5 < 11.9 mm, C6 < 12.3 mm, and C7 < 13.3 mm. Overall, 13.0% (262 of 2,019) of the population-based cohort had multilevel DcSS. Multilevel DcSS (odds ratio (OR) 6.12 (95% CI 3.97 to 9.42); p < 0.001) and male sex (OR 4.06 (95% CI 2.55 to 6.45); p < 0.001) were predictors of developing DCM. Conclusion. This is the first MRI-based study for defining DcSS with multilevel canal narrowing. Level-specific cut-off canal diameters for DcSS can be used for early identification of individuals at risk of developing DCM. Individuals with DcSS at ≥ three levels and male sex are recommended for close monitoring or early intervention to avoid traumatic spinal cord injuries from stenosis. Cite this article: Bone Joint J 2024;106-B(11):1333–1341


Bone & Joint Open
Vol. 4, Issue 3 | Pages 198 - 204
16 Mar 2023
Ramsay N Close JCT Harris IA Harvey LA

Aims. Cementing in arthroplasty for hip fracture is associated with improved postoperative function, but may have an increased risk of early mortality compared to uncemented fixation. Quantifying this mortality risk is important in providing safe patient care. This study investigated the association between cement use in arthroplasty and mortality at 30 days and one year in patients aged 50 years and over with hip fracture. Methods. This retrospective cohort study used linked data from the Australian Hip Fracture Registry and the National Death Index. Descriptive analysis and Kaplan-Meier survival curves tested the unadjusted association of mortality between cemented and uncemented procedures. Multilevel logistic regression, adjusted for covariates, tested the association between cement use and 30-day mortality following arthroplasty. Given the known institutional variation in preference for cemented fixation, an instrumental variable analysis was also performed to minimize the effect of unknown confounders. Adjusted Cox modelling analyzed the association between cement use and mortality at 30 days and one year following surgery. Results. The 30-day mortality was 6.9% for cemented and 4.9% for uncemented groups (p = 0.003). Cement use was significantly associated with 30-day mortality in the Kaplan-Meier survival curve (p = 0.003). After adjusting for covariates, no significant association between cement use and 30-day mortality was shown in the adjusted multilevel logistic regression (odd rati0 (OR) 1.1, 95% confidence interval (CI) 0.9 to 1.5; p = 0.366), or in the instrumental variable analysis (OR 1.0, 95% CI 0.9 to 1.0, p=0.524). There was no significant between-group difference in mortality within 30days (hazard ratio (HR) 0.9, 95% CI 0.7to 1.1; p = 0.355) or one year (HR 0.9 95% CI 0.8 to 1.1; p = 0.328) in the Cox modelling. Conclusion. No statistically significant difference in patient mortality with cement use in arthroplasty was demonstrated in this population, once adjusted for covariates. This study concludes that cementing in arthroplasty for hip fracture is a safe means of surgical fixation. Cite this article: Bone Jt Open 2023;4(3):198–204


Bone & Joint Open
Vol. 3, Issue 8 | Pages 611 - 617
1 Aug 2022
Frihagen F Comeau-Gauthier M Axelrod D Bzovsky S Poolman R Heels-Ansdell D Bhandari M Sprague S Schemitsch E

Aims. The aim of this study was to explore the functional results in a fitter subgroup of participants in the Hip Fracture Evaluation with Alternatives of Total Hip Arthroplasty versus Hemiarthroplasty (HEALTH) trial to determine whether there was an advantage of total hip arthroplasty (THA) versus hemiarthroplasty (HA) in this population. Methods. We performed a post hoc exploratory analysis of a fitter cohort of patients from the HEALTH trial. Participants were aged over 50 years and had sustained a low-energy displaced femoral neck fracture (FNF). The fittest participant cohort was defined as participants aged 70 years or younger, classified as American Society of Anesthesiologists grade I or II, independent walkers prior to fracture, and living at home prior to fracture. Multilevel models were used to estimate the effect of THA versus HA on functional outcomes. In addition, a sensitivity analysis of the definition of the fittest participant cohort was performed. Results. There were 143 patients included in the fittest cohort. Mean age was 66 years (SD 4.5) and 103 were female (72%). No clinically relevant differences were found between the treatment groups in the primary and sensitivity analyses. Conclusion. This analysis found no differences in functional outcomes between HA and THA within two years of displaced low-energy FNF in a subgroup analysis of the fittest HEALTH patients. These findings suggest that very few patients above 50 years of age benefit in a clinically meaningful way from a THA versus a HA early after injury. Cite this article: Bone Jt Open 2022;3(8):611–617


Bone & Joint Open
Vol. 3, Issue 3 | Pages 189 - 195
4 Mar 2022
Atwan Y Sprague S Slobogean GP Bzovsky S Jeray KJ Petrisor B Bhandari M Schemitsch E

Aims. To evaluate the impact of negative pressure wound therapy (NPWT) on the odds of having deep infections and health-related quality of life (HRQoL) following open fractures. Methods. Patients from the Fluid Lavage in Open Fracture Wounds (FLOW) trial with Gustilo-Anderson grade II or III open fractures within the lower limb were included in this secondary analysis. Using mixed effects logistic regression, we assessed the impact of NPWT on deep wound infection requiring surgical intervention within 12 months post-injury. Using multilevel model analyses, we evaluated the impact of NPWT on the Physical Component Summary (PCS) of the 12-Item Short-Form Health Survey (SF-12) at 12 months post-injury. Results. After applying inverse probability treatment weighting to adjust for the influence of injury characteristics on type of dressing used, 1,322 participants were assessed. The odds of developing a deep infection requiring operative management within 12 months of initial surgery was 4.52-times higher in patients who received NPWT compared to those who received a standard wound dressing (95% confidence interval (CI) 1.84 to 11.12; p = 0.001). Overall, 1,040 participants were included in our HRQoL analysis, and those treated with NPWT had statistically significantly lower mean SF-12 PCS post-fracture (p < 0.001). These differences did not reach the minimally important difference for the SF-12 PCS. Conclusion. Our analysis found that patients treated with NPWT had higher odds of developing a deep infection requiring operative management within 12 months post-fracture. Due to possible residual confounding with the worst cases being treated with NPWT, we are unable to determine if NPWT has a negative effect or is simply a marker of worse injuries or poor access to early soft-tissue coverage. Regardless, our results suggest that the use of this treatment requires further evaluation. Cite this article: Bone Jt Open 2022;3(3):189–195


The Bone & Joint Journal
Vol. 104-B, Issue 1 | Pages 59 - 67
1 Jan 2022
Kingsbury SR Smith LK Shuweihdi F West R Czoski Murray C Conaghan PG Stone MH

Aims. The aim of this study was to conduct a cross-sectional, observational cohort study of patients presenting for revision of a total hip, or total or unicompartmental knee arthroplasty, to understand current routes to revision surgery and explore differences in symptoms, healthcare use, reason for revision, and the revision surgery (surgical time, components, length of stay) between patients having regular follow-up and those without. Methods. Data were collected from participants and medical records for the 12 months prior to revision. Patients with previous revision, metal-on-metal articulations, or hip hemiarthroplasty were excluded. Participants were retrospectively classified as ‘Planned’ or ‘Unplanned’ revision. Multilevel regression and propensity score matching were used to compare the two groups. Results. Data were analyzed from 568 patients, recruited in 38 UK secondary care sites between October 2017 and October 2018 (43.5% male; mean (SD) age 71.86 years (9.93); 305 hips, 263 knees). No significant inclusion differences were identified between the two groups. For hip revision, time to revision > ten years (odds ratio (OR) 3.804, 95% confidence interval (CI) (1.353 to 10.694), p = 0.011), periprosthetic fracture (OR 20.309, 95% CI (4.574 to 90.179), p < 0.001), and dislocation (OR 12.953, 95% CI (4.014 to 41.794), p < 0.001), were associated with unplanned revision. For knee, there were no associations with route to revision. Revision after ten years was more likely for those who were younger at primary surgery, regardless of route to revision. No significant differences in cost outcomes, length of surgery time, and access to a health professional in the year prior to revision were found between the two groups. When periprosthetic fractures, dislocations, and infections were excluded, healthcare use was significantly higher in the unplanned revision group. Conclusion. Differences between characteristics for patients presenting for planned and unplanned revision are minimal. Although there was greater healthcare use in those having unplanned revision, it appears unlikely that routine orthopaedic review would have detected many of these issues. It may be safe to disinvest in standard follow-up provided there is rapid access to orthopaedic review. Cite this article: Bone Joint J 2022;104-B(1):59–67


Bone & Joint Open
Vol. 5, Issue 5 | Pages 435 - 443
23 May 2024
Tadross D McGrory C Greig J Townsend R Chiverton N Highland A Breakwell L Cole AA

Aims. Gram-negative infections are associated with comorbid patients, but outcomes are less well understood. This study reviewed diagnosis, management, and treatment for a cohort treated in a tertiary spinal centre. Methods. A retrospective review was performed of all gram-negative spinal infections (n = 32; median age 71 years; interquartile range 60 to 78), excluding surgical site infections, at a single centre between 2015 to 2020 with two- to six-year follow-up. Information regarding organism identification, antibiotic regime, and treatment outcomes (including clinical, radiological, and biochemical) were collected from clinical notes. Results. All patients had comorbidities and/or non-spinal procedures within the previous year. Most infections affected lumbar segments (20/32), with Escherichia coli the commonest organism (17/32). Causative organisms were identified by blood culture (23/32), biopsy/aspiration (7/32), or intraoperative samples (2/32). There were 56 different antibiotic regimes, with oral (PO) ciprofloxacin being the most prevalent (13/56; 17.6%). Multilevel, contiguous infections were common (8/32; 25%), usually resulting in bone destruction and collapse. Epidural collections were seen in 13/32 (40.6%). In total, five patients required surgery, three for neurological deterioration. Overall, 24 patients improved or recovered with a mean halving of CRP at 8.5 days (SD 6). At the time of review (two to six years post-diagnosis), 16 patients (50%) were deceased. Conclusion. This is the largest published cohort of gram-negative spinal infections. In older patients with comorbidities and/or previous interventions in the last year, a high level of suspicion must be given to gram-negative infection with blood cultures and biopsy essential. Early organism identification permits targeted treatment and good initial clinical outcomes; however, mortality is 50% in this cohort at a mean of 4.2 years (2 to 6) after diagnosis. Cite this article: Bone Jt Open 2024;5(5):435–443


The Bone & Joint Journal
Vol. 105-B, Issue 1 | Pages 35 - 46
1 Jan 2023
Mills K Wymenga AB Bénard MR Kaptein BL Defoort KC van Hellemondt GG Heesterbeek PJC

Aims

The aim of this study was to compare a bicruciate-retaining (BCR) total knee arthroplasty (TKA) with a posterior cruciate-retaining (CR) TKA design in terms of kinematics, measured using fluoroscopy and stability as micromotion using radiostereometric analysis (RSA).

Methods

A total of 40 patients with end-stage osteoarthritis were included in this randomized controlled trial. All patients performed a step-up and lunge task in front of a monoplane fluoroscope one year postoperatively. Femorotibial contact point (CP) locations were determined at every flexion angle and compared between the groups. RSA images were taken at baseline, six weeks, three, six, 12, and 24 months postoperatively. Clinical and functional outcomes were compared postoperatively for two years.


The Bone & Joint Journal
Vol. 106-B, Issue 1 | Pages 38 - 45
1 Jan 2024
Leal J Mirza B Davies L Fletcher H Stokes J Cook JA Price A Beard DJ

Aims

The aim of this study was to estimate the incremental use of resources, costs, and quality of life outcomes associated with surgical reconstruction compared to rehabilitation for long-standing anterior cruciate ligament (ACL) injury in the NHS, and to estimate its cost-effectiveness.

Methods

A total of 316 patients were recruited and randomly assigned to either surgical reconstruction or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment). Healthcare resource use and health-related quality of life data (EuroQol five-dimension five-level health questionnaire) were collected in the trial at six, 12, and 18 months using self-reported questionnaires and medical records. Using intention-to-treat analysis, differences in costs, and quality-adjusted life years (QALYs) between treatment arms were estimated adjusting for baseline differences and following multiple imputation of missing data. The incremental cost-effectiveness ratio (ICER) was estimated as the difference in costs divided by the difference in QALYs between reconstruction and rehabilitation.


The Bone & Joint Journal
Vol. 106-B, Issue 8 | Pages 858 - 864
1 Aug 2024
Costa ML Achten J Knight R Campolier M Massa MS

Aims

The aims of this study were to report the outcomes of patients with a complex fracture of the lower limb in the five years after they took part in the Wound Healing in Surgery for Trauma (WHIST) trial.

Methods

The WHIST trial compared negative pressure wound therapy (NPWT) dressings with standard dressings applied at the end of the first operation for patients undergoing internal fixation of a complex fracture of the lower limb. Complex fractures included periarticular fractures and open fractures when the wound could be closed primarily at the end of the first debridement. A total of 1,548 patients aged ≥ 16 years completed the initial follow-up, six months after injury. In this study we report the pre-planned analysis of outcome data up to five years. Patients reported their Disability Rating Index (DRI) (0 to 100, in which 100 = total disability), and health-related quality of life, chronic pain scores and neuropathic pain scores annually, using a self-reported questionnaire. Complications, including further surgery related to the fracture, were also recorded.


Bone & Joint Open
Vol. 4, Issue 5 | Pages 370 - 377
19 May 2023
Comeau-Gauthier M Bzovsky S Axelrod D Poolman RW Frihagen F Bhandari M Schemitsch E Sprague S

Aims

Using data from the Hip Fracture Evaluation with Alternatives of Total Hip Arthroplasty versus Hemiarthroplasty (HEALTH) trial, we sought to determine if a difference in functional outcomes exists between monopolar and bipolar hemiarthroplasty (HA).

Methods

This study is a secondary analysis of patients aged 50 years or older with a displaced femoral neck fracture who were enrolled in the HEALTH trial and underwent monopolar and bipolar HA. Scores from the Western Ontario and McMaster University Arthritis Index (WOMAC) and 12-Item Short Form Health Survey (SF-12) Physical Component Summary (PCS) and (MCS) were compared between the two HA groups using a propensity score-weighted analysis.


Aims

Ankle fracture fixation is commonly performed by junior trainees. Simulation training using cadavers may shorten the learning curve and result in a technically superior surgical performance.

Methods

We undertook a preliminary, pragmatic, single-blinded, multicentre, randomized controlled trial of cadaveric simulation versus standard training. Primary outcome was fracture reduction on postoperative radiographs.


Bone & Joint Open
Vol. 4, Issue 8 | Pages 602 - 611
21 Aug 2023
James HK Pattison GTR Griffin J Fisher JD Griffin DR

Aims

To evaluate if, for orthopaedic trainees, additional cadaveric simulation training or standard training alone yields superior radiological and clinical outcomes in patients undergoing dynamic hip screw (DHS) fixation or hemiarthroplasty for hip fracture.

Methods

This was a preliminary, pragmatic, multicentre, parallel group randomized controlled trial in nine secondary and tertiary NHS hospitals in England. Researchers were blinded to group allocation. Overall, 40 trainees in the West Midlands were eligible: 33 agreed to take part and were randomized, five withdrew after randomization, 13 were allocated cadaveric training, and 15 were allocated standard training. The intervention was an additional two-day cadaveric simulation course. The control group received standard on-the-job training. Primary outcome was implant position on the postoperative radiograph: tip-apex distance (mm) (DHS) and leg length discrepancy (mm) (hemiarthroplasty). Secondary clinical outcomes were procedure time, length of hospital stay, acute postoperative complication rate, and 12-month mortality. Procedure-specific secondary outcomes were intraoperative radiation dose (for DHS) and postoperative blood transfusion requirement (hemiarthroplasty).


Aims

To systematically review the efficacy of split tendon transfer surgery on gait-related outcomes for children and adolescents with cerebral palsy (CP) and spastic equinovarus foot deformity.

Methods

Five databases (CENTRAL, CINAHL, PubMed, Embase, Web of Science) were systematically screened for studies investigating split tibialis anterior or split tibialis posterior tendon transfer for spastic equinovarus foot deformity, with gait-related outcomes (published pre-September 2022). Study quality and evidence were assessed using the Methodological Index for Non-Randomized Studies, the Risk of Bias In Non-Randomized Studies of Interventions, and the Grading of Recommendations Assessment, Development and Evaluation.


Bone & Joint Open
Vol. 5, Issue 3 | Pages 184 - 201
7 Mar 2024
Achten J Marques EMR Pinedo-Villanueva R Whitehouse MR Eardley WGP Costa ML Kearney RS Keene DJ Griffin XL

Aims

Ankle fracture is one of the most common musculoskeletal injuries sustained in the UK. Many patients experience pain and physical impairment, with the consequences of the fracture and its management lasting for several months or even years. The broad aim of ankle fracture treatment is to maintain the alignment of the joint while the fracture heals, and to reduce the risks of problems, such as stiffness. More severe injuries to the ankle are routinely treated surgically. However, even with advances in surgery, there remains a risk of complications; for patients experiencing these, the associated loss of function and quality of life (Qol) is considerable. Non-surgical treatment is an alternative to surgery and involves applying a cast carefully shaped to the patient’s ankle to correct and maintain alignment of the joint with the key benefit being a reduction in the frequency of common complications of surgery. The main potential risk of non-surgical treatment is a loss of alignment with a consequent reduction in ankle function. This study aims to determine whether ankle function, four months after treatment, in patients with unstable ankle fractures treated with close contact casting is not worse than in those treated with surgical intervention, which is the current standard of care.

Methods

This trial is a pragmatic, multicentre, randomized non-inferiority clinical trial with an embedded pilot, and with 12 months clinical follow-up and parallel economic analysis. A surveillance study using routinely collected data will be performed annually to five years post-treatment. Adult patients, aged 60 years and younger, with unstable ankle fractures will be identified in daily trauma meetings and fracture clinics and approached for recruitment prior to their treatment. Treatments will be performed in trauma units across the UK by a wide range of surgeons. Details of the surgical treatment, including how the operation is done, implant choice, and the recovery programme afterwards, will be at the discretion of the treating surgeon. The non-surgical treatment will be close-contact casting performed under anaesthetic, a technique which has gained in popularity since the publication of the Ankle Injury Management (AIM) trial. In all, 890 participants (445 per group) will be randomly allocated to surgical or non-surgical treatment. Data regarding ankle function, QoL, complications, and healthcare-related costs will be collected at eight weeks, four and 12 months, and then annually for five years following treatment. The primary outcome measure is patient-reported ankle function at four months from treatment.


Bone & Joint Research
Vol. 11, Issue 4 | Pages 239 - 250
20 Apr 2022
Stewart CC O’Hara NN Bzovsky S Bahney CS Sprague S Slobogean GP

Aims

Bone turnover markers (BTMs) follow distinct trends after fractures and limited evidence suggests differential levels in BTMs in patients with delayed healing. The effect of vitamin D, and other factors that influence BTMs and fracture healing, is important to elucidate the use of BTMs as surrogates of fracture healing. We sought to determine whether BTMs can be used as early markers of delayed fracture healing, and the effect of vitamin D on BTM response after fracture.

Methods

A total of 102 participants aged 18 to 50 years (median 28 years (interquartile range 23 to 35)), receiving an intramedullary nail for a tibial or femoral shaft fracture, were enrolled in a randomized controlled trial comparing vitamin D3 supplementation to placebo. Serum C-terminal telopeptide of type I collagen (CTX; bone resorption marker) and N-terminal propeptide of type I procollagen (P1NP; bone formation marker) were measured at baseline, six weeks, and 12 weeks post-injury. Clinical and radiological fracture healing was assessed at three months.


The Bone & Joint Journal
Vol. 103-B, Issue 1 | Pages 18 - 25
1 Jan 2021
McNally M Sousa R Wouthuyzen-Bakker M Chen AF Soriano A Vogely HC Clauss M Higuera CA Trebše R

Aims

The diagnosis of periprosthetic joint infection (PJI) can be difficult. All current diagnostic tests have problems with accuracy and interpretation of results. Many new tests have been proposed, but there is no consensus on the place of many of these in the diagnostic pathway. Previous attempts to develop a definition of PJI have not been universally accepted and there remains no reference standard definition.

Methods

This paper reports the outcome of a project developed by the European Bone and Joint Infection Society (EBJIS), and supported by the Musculoskeletal Infection Society (MSIS) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Implant-Associated Infections (ESGIAI). It comprised a comprehensive review of the literature, open discussion with Society members and conference delegates, and an expert panel assessment of the results to produce the final guidance.


Bone & Joint Research
Vol. 7, Issue 2 | Pages 124 - 130
1 Feb 2018
Coric D Bullard DE Patel VV Ryaby JT Atkinson BL He D Guyer RD

Objectives

Pulsed electromagnetic field (PEMF) stimulation was evaluated after anterior cervical discectomy and fusion (ACDF) procedures in a randomized, controlled clinical study performed for United States Food and Drug Administration (FDA) approval. PEMF significantly increased fusion rates at six months, but 12-month fusion outcomes for subjects at elevated risk for pseudoarthrosis were not thoroughly reported. The objective of the current study was to evaluate the effect of PEMF treatment on subjects at increased risk for pseudoarthrosis after ACDF procedures.

Methods

Two evaluations were performed that compared fusion rates between PEMF stimulation and a historical control (160 subjects) from the FDA investigational device exemption (IDE) study: a post hoc (PH) analysis of high-risk subjects from the FDA study (PH PEMF); and a multicentre, open-label (OL) study consisting of 274 subjects treated with PEMF (OL PEMF). Fisher’s exact test and multivariate logistic regression was used to compare fusion rates between PEMF-treated subjects and historical controls.


The Bone & Joint Journal
Vol. 99-B, Issue 3 | Pages 383 - 392
1 Mar 2017
Handoll HH Keding A Corbacho B Brealey SD Hewitt C Rangan A

Aims

The PROximal Fracture of the Humerus Evaluation by Randomisation (PROFHER) randomised clinical trial compared the operative and non-operative treatment of adults with a displaced fracture of the proximal humerus involving the surgical neck. The aim of this study was to determine the long-term treatment effects beyond the two-year follow-up.

Patients and Methods

Of the original 250 trial participants, 176 consented to extended follow-up and were sent postal questionnaires at three, four and five years after recruitment to the trial. The Oxford Shoulder Score (OSS; the primary outcome), EuroQol 5D-3L (EQ-5D-3L), and any recent shoulder operations and fracture data were collected. Statistical and economic analyses, consistent with those of the main trial were applied.


Bone & Joint Research
Vol. 7, Issue 3 | Pages 223 - 225
1 Mar 2018
Jones LD Golan D Hanna SA Ramachandran M


Bone & Joint Research
Vol. 7, Issue 5 | Pages 343 - 350
1 May 2018
He A Ning Y Wen Y Cai Y Xu K Cai Y Han J Liu L Du Y Liang X Li P Fan Q Hao J Wang X Guo X Ma T Zhang F

Aim

Osteoarthritis (OA) is caused by complex interactions between genetic and environmental factors. Epigenetic mechanisms control the expression of genes and are likely to regulate the OA transcriptome. We performed integrative genomic analyses to define methylation-gene expression relationships in osteoarthritic cartilage.

Patients and Methods

Genome-wide DNA methylation profiling of articular cartilage from five patients with OA of the knee and five healthy controls was conducted using the Illumina Infinium HumanMethylation450 BeadChip (Illumina, San Diego, California). Other independent genome-wide mRNA expression profiles of articular cartilage from three patients with OA and three healthy controls were obtained from the Gene Expression Omnibus (GEO) database. Integrative pathway enrichment analysis of DNA methylation and mRNA expression profiles was performed using integrated analysis of cross-platform microarray and pathway software. Gene ontology (GO) analysis was conducted using the Database for Annotation, Visualization and Integrated Discovery (DAVID).