Aims: Early large treatment effects can arise in small studies, which lessen as more data accumulate. This study aimed to retrospectively examine whether early treatment effects occurred for two multicentre orthopaedic randomized controlled trials (RCTs) and explore biases related to this. Methods: Included RCTs were ProFHER (PROximal Fracture of the Humerus: Evaluation by Randomisation), a two-arm study of surgery versus non-surgical treatment for proximal humerus fractures, and UK FROST (United Kingdom Frozen Shoulder Trial), a three-arm study of two surgical and one non-surgical treatment for frozen shoulder. To determine whether early treatment effects were present, the primary outcome of Oxford Shoulder Score (OSS) was compared on forest plots for: the chief investigator’s (CI) site to the remaining sites, the first five sites opened to the other sites, and patients grouped in quintiles by randomization date. Potential for bias was assessed by comparing mean age and proportion of patients with indicators of poor outcome between included and excluded/non-consenting participants. Results: No bias in treatment effect was observed overall for the CI site, or the first five sites, compared with the remaining sites in either trial. An early treatment effect on the OSS was observed for the first quintile of participants recruited to ProFHER only (clinically relevant difference of seven points). Selection bias for age was observed in the ProFHER trial only, with slightly younger patients being recruited into the study. Both trials showed some selection bias for markers of poor prognosis, although these did not appear to change over time. Conclusion: No bias in treatment effects overall were found at the CI or early sites set-up. An early treatment effect was found in one of the two trials, which was likely a chance effect as this did not continue during the study. Selection bias was observed in both RCTs, however this was minimal and did not impact on outcome. Cite this article: Bone Jt Open 2023;4(2):96–103.

Aims Frozen shoulder and proximal humeral fracture can cause pain, stiffness and loss of function. The impact of these symptoms on patients can be measured using the comprehensively validated, 12-item Oxford Shoulder Score (OSS). Evidence suggests that pain and function may have a differential impact on patients’ experience of shoulder conditions, and this may be important for clinical management. We therefore explored the factor structure of the OSS within the UK FROST and PROFHER trial populations. Methods We performed exploratory factor analysis (EFA), followed by confirmatory factor analysis (CFA), on baseline UK FROST data from 490 of the 503 trial participants. Data at 6 months post-randomisation were used for 228 of the 250 participants for the PROFHER trial. Results UK FROST factor extraction results, using Velicer's Minimum Average Partial and Horn's Parallel Analysis tests, suggested a unifactorial solution, but two factors were weakly indicated by the less reliable ‘Kaiser’s eigenvalue > 1’ and scree tests. We explored this further using EFA. Eight items (2 to 7, 9 and 10) loaded onto a ‘Function’ factor, three on a ‘Pain’ factor (1, 8 and 12) and item 11 cross-loaded. However, one- and two-factor models were rejected in CFA. Factor extraction of PROFHER data at 6 months demonstrated a single first-order factor solution, which was also subsequently rejected in CFA. Conclusion Insufficient evidence was found, within the constraints of the data available, to support the use of ‘Pain’ and ‘Function’ sub-scales of the OSS in either patient population.

Aims: A pilon fracture is a severe ankle joint injury caused by high-energy trauma, typically affecting men of working age. Although relatively uncommon (5% to 7% of all tibial fractures), this injury causes among the worst functional and health outcomes of any skeletal injury, with a high risk of serious complications and long-term disability, and with devastating consequences on patients’ quality of life and financial prospects. Robust evidence to guide treatment is currently lacking. This study aims to evaluate the clinical and cost-effectiveness of two surgical interventions that are most commonly used to treat pilon fractures. Methods: A randomized controlled trial (RCT) of 334 adult patients diagnosed with a closed type C pilon fracture will be conducted. Internal locking plate fixation will be compared with external frame fixation. The primary outcome and endpoint will be the Disability Rating Index (a patient self-reported assessment of physical disability) at 12 months. This will also be measured at baseline, three, six, and 24 months after randomization. Secondary outcomes include the Olerud and Molander Ankle Score (OMAS), the five-level EuroQol five-dimenison score (EQ-5D-5L), complications (including bone healing), resource use, work impact, and patient treatment preference. The acceptability of the treatments and study design to patients and health care professionals will be explored through qualitative methods. Discussion: The two treatments being compared are the most commonly used for this injury, however there is uncertainty over which is most clinically and cost-effective. The Articular Pilon Fracture (ACTIVE) Trial is a sufficiently powered and rigorously designed study to inform clinical decisions for the treatment of adults with this injury. Cite this article: Bone Jt Open 2021;2(3):150–163.

Aims A pragmatic multicentre randomized controlled trial, UK FROzen Shoulder Trial (UK FROST), was conducted in the UK NHS comparing the cost-effectiveness of commonly used treatments for adults with primary frozen shoulder in secondary care. Methods A cost utility analysis from the NHS perspective was performed. Differences between manipulation under anaesthesia (MUA), arthroscopic capsular release (ACR), and early structured physiotherapy plus steroid injection (ESP) in costs (2018 GBP price base) and quality adjusted life years (QALYs) at one year were used to estimate the cost-effectiveness of the treatments using regression methods. Results ACR was £1,734 more costly than ESP ((95% confidence intervals (CIs) £1,529 to £1,938)) and £1,457 more costly than MUA (95% CI £1,283 to £1,632). MUA was £276 (95% CI £66 to £487) more expensive than ESP. Overall, ACR had worse QALYs compared with MUA (-0.0293; 95% CI -0.0616 to 0.0030) and MUA had better QALYs compared with ESP (0.0396; 95% CI -0.0008 to 0.0800). At a £20,000 per QALY willingness-to-pay threshold, MUA had the highest probability of being cost-effective (0.8632) then ESP (0.1366) and ACR (0.0002). The results were robust to sensitivity analyses. Conclusion While ESP was less costly, MUA was the most cost-effective option. ACR was not cost-effective. Cite this article: Bone Jt Open 2021;2(8):685–695.

Aims The aim of this study was to explore whether time to surgery affects functional outcome in displaced proximal humeral fractures Methods A total of 250 patients presenting within three weeks of sustaining a displaced proximal humeral fracture involving the surgical neck were recruited at 32 acute NHS hospitals in the United Kingdom between September 2008 and April 2011. Of the 125 participants, 109 received surgery (fracture fixation or humeral head replacement) as per randomization. Data were included for 101 and 67 participants at six-month and five-year follow-up, respectively. Oxford Shoulder Scores (OSS) collected at six, 12, and 24 months and at three, four, and five years following randomization was plotted against time to surgery. Long-term recovery was explored by plotting six-month scores against five-year scores and agreement was illustrated with a Bland-Altman plot. Results The mean time from initial trauma to surgery was 10.5 days (1 to 33). Earlier surgical intervention did not improve OSS throughout follow-up, nor when stratified by participant age (< 65 years vs ≥ 65 years) and fracture severity (one- and two-part vs three- and four-part fractures). Participants managed later than reported international averages (three days in the United States and Germany, eight days in the United Kingdom) did not have worse outcomes. At five-year follow-up, 50 participants (76%) had the same or improved OSS compared with six months (six-month mean OSS 35.8 (SD 10.0); five-year mean OSS 40.1 (SD 9.1); r = 0.613). A Bland-Altman plot demonstrated a positive mean difference (3.3 OSS points (SD 7.92)) with wide 95% limits of agreement (-12.2 and 18.8 points). Conclusion Timing of surgery did not affect OSS at any stage of follow-up, irrespective of age or fracture type. Most participants had maximum functional outcome at six months that was maintained at five years. These findings may help guide providers of trauma services on surgical prioritization. Cite this article: Bone Joint J 2020;102-B(1):33–41

To increase the knowledge about the performance of the five-level version (5L) of the EuroQol EQ-5D quality of life instrument. participants (n=151) aged over 70 from REFORM (REducing Falls with Orthoses and a Multifaceted podiatry intervention) trial completed the 3L and 5L instruments. Both instruments were assessed in terms of feasibility, reliability, validity, and efficiency for trial design. completeness was higher for the 5L (96.7%) than for the 3L (92.7%). The proportion of inconsistent responses between both instruments was 3.25%. Redistribution from 3L to 5L showed valid results. For the 5L, 67 unique health states were observed compared with 27 for the 3L. The ceiling effect was reduced from 11.2% (3L) to 6% (5L). The absolute informativity (1.58 for 5L versus 0.97 for 3L) and relative discriminatory power (0.68 for 5L versus 0.61 for 3L) improved with the 5L. Variance of the index scores was lower for the 5L (σ2=0.040) than 3L (σ2=0.056). our study supported the feasibility and validity of both instruments. However the 5L reduces ceiling effect and improves discriminatory power. The 5L could allow for more efficient sample size estimation and help to ameliorate missing data problem in cost-effectiveness analysis.

Purpose: Symptomatic hand osteoarthritis (OA) represents a considerable economic, clinical and social burden, and has limited treatment options. Synovitis is prevalent in OA and associated with pain. Hydroxychloroquine (HCQ) is used routinely for treating synovitis in inflammatory arthritides such as rheumatoid arthritis. The primary aim of the HERO RCT was to determine the effectiveness of HCQ as an analgesic treatment for hand OA, and secondarily to determine if synovitis was associated with treatment response, effects on structural progression and cost-effectiveness. Methods: Symptomatic hand osteoarthritis (OA) represents a considerable economic, clinical and social burden, and has limited treatment options. Synovitis is prevalent in OA and associated with pain. Hydroxychloroquine (HCQ) is used routinely for treating synovitis in inflammatory arthritides such as rheumatoid arthritis. The primary aim of the HERO RCT was to determine the effectiveness of HCQ as an analgesic treatment for hand OA, and secondarily to determine if synovitis was associated with treatment response, effects on structural progression and cost-effectiveness. Results: Follow-up was 84.7% at 6 months and 76.6% at 12 months. The mean initial HCQ dose for the intervention arm (n= 114) was 320 mg. At the primary endpoint, the treatment difference estimate between HCQ and Placebo was -0.16 points on the NRS pain scale (95% CI: -0.72 to 0.41, p=0.584, Table 1). There were no significant treatment differences at 3, 6 or 12 months for any secondary outcomes including radiographic outcomes (Table 1). Baseline structural damage did not affect response to HCQ. On ultrasound, 94% had ≥1 joint positive for greyscale synovitis, 59% were Power Doppler positive; synovitis did not impact on treatment group differences. The economic analysis found that HCQ was less costly but produced a smaller quality-adjusted life year (QALY) gain than placebo, saving £6,545 per QALY lost, and was not considered to be cost-effective. Conclusions: HCQ was not more effective than placebo in reducing symptoms or radiographic progression in people selected for moderate to severe hand pain and radiographic OA; HCQ is therefore not recommended for this patient group. Given the analgesic benefits of other anti-inflammatory therapies, these findings may reflect the mild anti-inflammatory action of HCQ, differing drug effects on certain OA pathologies, and also inclusion criteria in hand OA trials, where ultrasound-synovitis may not be as prevalent as in knee OA.

Objectives To explore whether orthopaedic surgeons have adopted the Proximal Fracture of the Humerus: Evaluation by Randomisation (PROFHER) trial results routinely into clinical practice. Methods A questionnaire was piloted with six orthopaedic surgeons using a ‘think aloud’ process. The final questionnaire contained 29 items and was distributed online to surgeon members of the British Orthopaedic Association and British Elbow and Shoulder Society. Descriptive statistics summarised the sample characteristics and fracture treatment of respondents overall, and grouped them by whether they changed practice based on PROFHER trial findings. Free-text responses were analysed qualitatively for emerging themes using Framework Analysis principles. Results There were complete responses from 265 orthopaedic and trauma surgeons who treat patients with proximal humeral fractures. Around half (137) had changed practice to various extents because of PROFHER, by operating on fewer PROFHER-eligible fractures. A third (43) of the 128 respondents who had not changed practice were already managing patients non-operatively. Those who changed practice were more likely to be younger, work in a trauma unit rather than a major trauma centre, be specialist shoulder surgeons and treat fewer PROFHER-eligible fractures surgically. This group gave higher scores when assessing validity and applicability of PROFHER. In contrast, a quarter of the non-changers were critical, sometimes emphatically, of PROFHER. The strongest theme that emerged overall was the endorsement of evidence-based practice. Conclusion PROFHER has had an impact on surgeons’ clinical practice, both through changing it, and through underpinning existing non-operative practice. Although some respondents expressed reservations about the trial, evidence from such trials was found to be the most important influence on surgeons’ decisions to change practice. Cite this article: L. Jefferson, S. Brealey, H. Handoll, A. Keding, L. Kottam, I. Sbizzera, A. Rangan. Impact of the PROFHER trial findings on surgeons’ clinical practice: An online questionnaire survey. Bone Joint Res 2017;6:590–599. DOI: 10.1302/2046-3758.610.BJR-2017-0170.

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. Results OSS data were available for 164, 155 and 149 participants at three, four and five years, respectively. There were no statistically or clinically significant differences between operative and non-operative treatment at each follow-up point. No participant had secondary shoulder surgery for a new complication. Analyses of EQ-5D-3L data showed no significant between-group differences in quality of life over time. Conclusion These results confirm that the main findings of the PROFHER trial over two years are unchanged at five years. Cite this article: Bone Joint J 2017;99-B:383–92.

The authors regret that there was an error in the above article where the text for the introduction section has been printed under both introduction and methods and the methods section omitted. The correct text for both sections is as follows: Purpose: Symptomatic hand osteoarthritis (OA) represents a considerable economic, clinical and social burden, and has limited treatment options. Synovitis is prevalent in OA and associated with pain. Hydroxychloroquine (HCQ) is used routinely for treating synovitis in inflammatory arthritides such as rheumatoid arthritis. The primary aim of the HERO RCT was to determine the effectiveness of HCQ as an analgesic treatment for hand OA, and secondarily to determine if synovitis was associated with treatment response, effects on structural progression and cost-effectiveness. Methods: 248 participants with symptomatic (visual analogue scale (VAS) pain ≥4/10) and radiographic hand OA were recruited across UK primary and secondary care and randomized to HCQ or placebo for 12 months. Daily HCQ dose ranged from 200 to 400 mg according to ideal body weight. The primary endpoint was average hand pain during the previous 2 weeks (numerical rating scale, NRS) at 6 months. Secondary endpoints included other self-reported pain and function scales (NRS and VAS scales, AUSCAN), grip strength, quality-of-life measures (OAQol, SF-12) and radiographic structural change (Kallman score) at 12 months. The effects of baseline radiographic severity were also assessed. In a sub-study, n = 143 participants had ultrasound performed at baseline on small joints of a single hand. Longitudinal mixed models compared changes between groups. Analyses were conducted on intention-to-treat basis. A health economics analysis was also performed. The authors would like to apologise for any inconvenience caused.

AIMS:A pragmatic multicentre randomised controlled trial (PROFHER) was conducted in United Kingdom National Health Service (NHS) hospitals to evaluate the clinical effectiveness and cost effectiveness of surgery compared with non-surgical treatment for displaced fractures of the proximal humerus involving the surgical neck in adults. METHODS:A cost utility analysis from the NHS perspective was performed. Differences between surgical and non-surgical treatment groups in costs and quality adjusted life years (QALYs) at two years were used to derive an estimate of the cost effectiveness of surgery using regression methods. RESULTS:Patients randomised to receive surgical intervention accumulated mean greater costs and marginally lower QALYs than patients randomised to non-surgery. The surgical intervention cost a mean of £1758 more per patient (95% confidence intervals (CI) £1126 to £2389). Total QALYs for the surgical group were smaller than those for non-surgery -0.0101 (95% CI -0.13 to 0.11). The probability of surgery being cost effective was less than 10% given the current NICE willingness to pay at a threshold of £20 000 for an additional QALY. The results were robust to sensitivity analyses. DISCUSSION:The results suggest that current surgical treatment is not cost effective for the majority of displaced fractures of the proximal humerus involving the surgical neck in the United Kingdom's NHS. TAKE HOME MESSAGE:The results of this trial do not support the trend of increased surgical treatment for patients with displaced fractures of the proximal humerus involving the surgical neck within the United Kingdom NHS.

Background: Tailoring neoadjuvant chemotherapy (NAC) during breast cancer treatment is performed to improve overall tumour response, with increasing evidence to support its role. This study evaluates our breast unit's experience in MRI assessment of tumour response as an aid in tailoring NAC.Materials and methods: This is a retrospective study of patients treated with NAC for breast cancer between 2005 and 2009 who underwent MRI to assess tumour response. Response to NAC was monitored before NAC and after 2 and/or 4 cycles of anthracycfine and cyclophosphamide (AC) chemotherapy. Taxane was substituted for AC if MRI response was deemed inadequate. Tumour response on last MRI was correlated with final pathology against different tumour subtypes and in inflammatory tumours. Strength of agreement was measured using Kappa analysis. Potential predictive factors for MRI response were assessed for significance.Results: 166 tumours were assessed with serial MRI scans. MRI showed high sensitivity rate (93.1%) in predicting response to NAC particularly for tumours showing partial (PR) or complete (CR) response on pathology (p < 0.001) with fair agreement on Kappa analysis (K = 0.31). MRI seems more accurate in triple negative, HR+/HER2+ and high-grade tumours. Early identification of non-responders on MRI resulted in early tailoring of NAC, with improved rates of tumour response seen in 74.2% following switching NAC. Logistic regression showed that PR or CR observed on MRI after 2 NAC cycles significantly predicted pCR (p < 0.001).Conclusion: Serial MRI can be used to assess patterns of tumour response to NAC. This study shows that tailoring NAC according to pattern of response can improve overall tumour response rates. (C) 2016 Elsevier Ltd. All rights reserved.

Objectives Accurate characterisation of fractures is essential in fracture management trials. However, this is often hampered by poor inter-observer agreement. This article describes the practicalities of defining the fracture population, based on the Neer classification, within a pragmatic multicentre randomised controlled trial in which surgical treatment was compared with non-surgical treatment in adults with displaced fractures of the proximal humerus involving the surgical neck. Methods The trial manual illustrated the Neer classification of proximal humeral fractures. However, in addition to surgical neck displacement, surgeons assessing patient eligibility reported on whether either or both of the tuberosities were involved. Anonymised electronic versions of baseline radiographs were sought for all 250 trial participants. A protocol, data collection tool and training presentation were developed and tested in a pilot study. These were then used in a formal assessment and classification of the trial fractures by two independent senior orthopaedic shoulder trauma surgeons. Results Two or more baseline radiographic views were obtained for each participant. The independent raters confirmed that all fractures would have been considered for surgery in contemporaneous practice. A full description of the fracture population based on the Neer classification was obtained. The agreement between the categorisation at baseline (tuberosity involvement) and Neer classification as assessed by the two raters was only fair (kappa 0.29). However, this disparity did not appear to affect trial findings, specifically in terms of influencing the effect of treatment on the primary outcome of the trial. Conclusions A key reporting requirement, namely the description of the fracture population, was achieved within the context of a pragmatic multicentre randomised clinical trial. This article provides important guidance for researchers designing similar trials on fracture management. Cite this article: H. H. G. Handoll, S. D. Brealey, L. Jefferson, A. Keding, A. J. Brooksbank, A. J. Johnstone, J. J. Candal-Couto, A. Rangan. Defining the fracture population in a pragmatic multicentre randomised controlled trial: PROFHER and the Neer classification of proximal humeral fractures.Bone Joint Res 2016;5:481–489. DOI: 10.1302/2046-3758.510.BJR-2016-0132.R1.

Objectives A rigorous approach to developing, delivering and documenting rehabilitation within randomised controlled trials of surgical interventions is required to underpin the generation of reliable and usable evidence. This article describes the key processes used to ensure provision of good quality and comparable rehabilitation to all participants of a multi-centre randomised controlled trial comparing surgery with conservative treatment of proximal humeral fractures in adults. Methods These processes included the development of a patient information leaflet on self-care during sling immobilisation, the development of a basic treatment physiotherapy protocol that received input and endorsement by specialist physiotherapists providing patient care, and establishing an expectation for the provision of home exercises. Specially designed forms were also developed to facilitate reliable reporting of the physiotherapy care that patients received. Results All three initiatives were successfully implemented, alongside the measures to optimise the documentation of physiotherapy. Thus, all participating sites that recruited patients provided the sling immobilisation leaflet, all adhered to the physiotherapy protocol and all provided home exercises. There was exemplary completion of the physiotherapy forms that often reflected a complex patient care pathway. These data demonstrated equal and high access to and implementation of physiotherapy between groups, including the performance of home exercises. Conclusion In order to increase the validity and relevance of the evidence from trials of surgical interventions and meet international reporting standards, careful attention to study design, conduct and reporting of the intrinsic rehabilitation components is required. The involvement of rehabilitation specialists is crucial to achieving this. Cite this article: Bone Joint Res 2014;3:335–40.

BACKGROUND:Depression with comorbid pain is associated with a poor response to various treatments. The objective in this secondary analysis was to determine whether patients reporting pain have different depression and pain outcomes over time in response to acupuncture, counselling or usual care. METHODS:Self-reported ratings of depression and pain from 755 patients in a pragmatic randomised controlled trial of acupuncture (302) or counselling (302) compared to usual care alone (151) are described and analysed using a series of regression models and analysis of covariance. Patient-reported outcomes of Patient Health Questionnaire (PHQ)-9 for depression, SF36 bodily pain and EQ-5D, all at baseline, 3, 6, 9 and 12 months. RESULTS:At baseline, 755 patients reported EQ-5D pain categories; 384 (50.9%) reported moderate-to-extreme pain. Controlling for baseline depression, a linear regression model showed that the presence of pain at baseline was associated with poorer depression outcomes at 3 months mean difference=-1.16, (95% CI 0.12 to 2.2). Participants with moderate-to-extreme pain at baseline did better at 3 months if they received acupuncture (mean reduction in Patient Health Questionnaire 9 (PHQ-9) from baseline=6.0, 95% CI 5.0 to 7.1 and a mean reduction in SF-36 bodily pain=11.2, (95% CI 7.1 to 15.2) compared to improvements for those who received counselling (4.3, 95% CI 3.3 to 5.4; 7.6, 95% CI 3.6 to 11.6) or usual care (2.7, 95% CI 1.50 to 4.0: 7.2, 95% CI 2.3 to 12.1). In comparison, no notable differences were seen between treatment arms within the no pain comparator group. CONCLUSIONS:Patients with depression and pain at baseline recovered less well from treatment over 3 months than those with depression and no pain. Reductions in both depression and pain were most marked in the acupuncture group, followed by the counselling group and then the usual care group.