Abstract
Aims
The aim of this study was to evaluate the epidemiology and treatment of Perthes’ disease of the hip.
Methods
This was an anonymized comprehensive cohort study of Perthes’ disease, with a nested consented cohort. A total of 143 of 144 hospitals treating children’s hip disease in the UK participated over an 18-month period. Cases were cross-checked using a secondary independent reporting network of trainee surgeons to minimize those missing. Clinician-reported outcomes were collected until two years. Patient-reported outcome measures (PROMs) were collected for a subset of participants.
Results
Overall, 371 children (396 hips) were newly affected by Perthes’ disease arising from 63 hospitals, with a median of two patients (interquartile range 1.0 to 5.5) per hospital. The annual incidence was 2.48 patients (95% confidence interval (CI) 2.20 to 2.76) per 100,000 zero- to 14-year-olds. Of these, 117 hips (36.4%) were treated surgically. There was considerable variation in the treatment strategy, and an optimized decision tree identified joint stiffness and age above eight years as the key determinants for containment surgery. A total of 348 hips (88.5%) had outcomes to two years, of which 227 were in the late reossification stage for which a hip shape outcome (Stulberg grade) was assigned. The independent predictors of a poorer radiological outcome were female sex (odds ratio (OR) 2.27 (95% CI 1.19 to 4.35)), age above six years (OR 2.62 (95% CI (1.30 to 5.28)), and over 50% radiological collapse at inclusion (OR 2.19 (95% CI 0.99 to 4.83)). Surgery had no effect on radiological outcomes (OR 1.03 (95% CI 0.55 to 1.96)). PROMs indicated the marked effect of the disease on the child, which persisted at two years.
Conclusion
Despite the frequency of containment surgery, we found no evidence of improved outcomes. There appears to be a sufficient case volume and community equipoise among surgeons to embark on a randomized clinical trial to definitively investigate the effectiveness of containment surgery.
Cite this article: Bone Joint J 2022;104-B(4):510–518.
Take home message
There is marked variation in the treatment of Perthes' disease, which is poorly explained, though it appears to relate to clinical uncertainties in the optimum treatment approach.
We found no evidence to support improved outcomes among children undergoing containment surgery.
Introduction
Perthes’ disease is an idiopathic avascular necrosis of a developing femoral head which occurs predominantly in males (at a ratio of 4:1) between four and eight years old.1,2 The disease usually results in long-term deformity of the hip, which is a major precipitant of premature osteoarthritis, and frequently necessitates hip arthroplasty in early adulthood.3 However, it is one of the most common and most poorly understood disorders encountered by paediatric orthopaedic surgeons. The incidence is believed to be approximately five per 100,000 zero- to 14-year-olds per year,4,5 suggesting that there are approximately 500 new cases throughout the UK annually. The origins of the disease are very closely linked to socioeconomic deprivation,2,5-7 though the aetiology and mechanism are so far unknown.
There is substantial variation in the treatment of Perthes’ disease, which includes observation without any intervention, admission to hospital for ‘traction’, several years of non-weightbearing in a wheelchair, months of enforced rest in abduction plaster casts, or surgery involving femoral and/or pelvic osteotomies.8 There are no randomized controlled trials (RCTs) to guide treatment, and only two cohort studies have sought to prospectively identify the outcomes of children with Perthes’ disease.9,10 There are few prognostic indicators to guide treatment; therefore, treatment is largely guided by the opinion of the treating surgeon. This has prompted the British Society of Children’s Orthopaedic Surgery and a James Lind Priority Setting Partnership to identify the treatment of Perthes’ disease as one of the top research priorities in children’s orthopaedic surgery.11,12
The low quality of evidence in surgery prompted the development of a framework to guide surgical research; the Idea, Development, Exploration, Assessment, Long-term study (IDEAL) framework.13-15 In this paper, we describe a national cohort study of children with Perthes’ disease that follows the IDEAL recommendations (IDEAL Stage 2b, ‘Exploration’). The aim was to explore the epidemiology and treatment of Perthes’ disease by investigating the disease frequency, case mix, technical intervention variables, surgeon and patient-reported outcomes, as well as safety of the patient.
Methods
We prospectively identified a national cohort of skeletally immature individuals with a confirmed radiological diagnosis of Perthes’ disease, defined using the typical radiological features within the femoral epiphysis: flattening, sclerosis, fragmentation, collapse, and reossification. Features could be evident on either plain radiographs or MRI. Participants were eligible for inclusion at the point of diagnosis by the clinician who made the treament decisions. Exclusion criteria included prior treatment for developmental hip dysplasia (not including double nappies), prior chemotherapy, sickle cell anaemia, multiple epiphyseal dysplasia, spondyloepiphyseal dysplasia, a known coagulopathy, hypothyroidism, Gaucher disease, or a previous same-sided hip fracture.
The defined population was zero- to 14-year-olds within the geographical boundaries of Great Britain. Patients were identified between 4 April 2016 and 30 September 2017. Data were collected through a national surveillance programme, the British Orthopaedic Surgery Surveillance (BOSS) study, using a bespoke electronic platform. The full protocol detailing the mechanism of data collection has been published previously.16 All but one hospital in the UK that treats any hip disease in childhood agreed to participate in the study (n = 143). Patients were identified prospectively by clinical teams who, following the initial admission, completed an electronic patient record form providing the patients’ disease presentation and surgery. Patients who had been potentially missed were identified monthly by integrating reports from an independent network of trainee surgeons, and were then automatically cross-checked with known reported cases; at the same time other potential patients were identified.
Each month, an automated email was sent to nominated reporting clinicians in each hospital to ask them to verify and confirm the completeness of their monthly case uploads, including confirmation of a null report. In addition, the email highlighted potential missed patients who had been identified by the trainees. The reporting clinicians were then invited to upload the missing details or indicate a false identification. The email also identified when follow-up was due. Surgeon follow-up was at one year and two years post-diagnosis to identify outcomes, principally the radiological appearance of the hip, the need for further surgery, and the development of contralateral disease.
Patient-reported outcome measures (PROMs) were collected at a subset of hospitals recruiting patients to the study. While surgeons entered anonymous patient details to collect surgeon-reported outcomes from diagnosis, patients could be enrolled at any time during the two years of follow-up to contribute patient-reported data. The PROMs collected were the Paediatric Quality of Life Inventory (PedsQL),17 the youth version of the EuroQol five-dimension three-level questionnaire (EQ-5D-Y),18 and the Wong-Baker FACES Pain Rating Scale.19
The study was registered on the ISCTRN registry (ISRCTN54477575) and is reported in accordance with the IDEAL reporting guidelines.20 Parent representatives from the Perthes’ Association and STEPS Worldwide, the primary charitable support groups for affected children and families, coproduced the work from prefunding until publication throughout the five-year study period. The Alder Hey NIHR Young Person’s Advisory Group (YPAG), a group of children and young people involved in improving the conduct of research in children, were also involved throughout the progress of the study. The YPAG have assisted in the development of this paper and digital participant information materials, advised on conduct during interval study updates, and are engaged in the dissemination of this work to patients and the public through animations and infographics.
Data collected
Clinicians were asked to give details regarding the following factors believed to be associated with prognosis: hip stiffness defined as ‘significantly limited abduction’ in the clinic environment; the radiological integrity of the lateral pillar;21 and the percentage of head involvement on the lateral radiograph.22 Clinicians were also asked to determine the radiological stage of disease using the modified Waldenström classification.23 At one- and two-year follow-up, the treatment received and outcomes were collected. The radiological outcome of ‘hip shape’ was collected if the hip was stated to be a modified Waldenström Stage 3B or beyond. The hip shape was assessed using the consensus algorithm developed by Neyt et al24 to describe the Stulberg classification. For hips for which follow-up radiographs were available, the roundness error on the anteroposterior (AP) radiograph was measured by an observer (DCP), who was blind to the reports from the Stulberg classification algorithm determined by participating surgeons.25
Statistical analysis
The statistical analysis plan was finalized prior to data lock. Percentages were calculated, excluding missing data. Incidence rates for first presentation of Perthes’ disease (no prior diagnosis in either hip) were calculated stratified by country, region, age, and sex, using cases identified between 1 June 2016 and 31 August 2017. This interval was used allowing for a ‘run-in period’ and ‘tail-off period’ in terms of case ascertainment. Denominators were taken to be the 2016 mid-year Office for National Statistical population estimates.26 Poisson 95% confidence intervals (CIs) for incidence rates were calculated. The cohort’s baseline characteristics were summarized together with the initial treatment strategy. For patients with a treatment plan in place, we derived binary decision-making cut-offs most likely to influence surgical versus non-surgical strategies, using recursive partitioning. These were compared to a prior understanding of what the decision process was thought to be. We summarized the treatments received and the stage of disease of hips at one- and two-year follow-up. For hips at stages 2B or higher, we used multivariable analyses to investigate effects of baseline and treatment factors on two-year radiological outcome. For each outcome modelled, we included key known predictors specified a priori, and other baseline variables found to be associated with the outcome on univariable analysis. Roundness error was modelled using random effects linear regression, and Stulberg grade was modelled using random effects ordinal logistic regression. Risk of contralateral Perthes’ disease was estimated with the associated 95% CIs. PROMs were summarized graphically over time. Univariate analyses were used to investigate associations between baseline factors and two-year PROMs. A p-value < 0.05 was considered significant.
Results
A total of 371 children (396 hips) had a new confirmed radiological diagnosis of Perthes’ disease identified during the 18-month recruitment period. Patients were provided from 63 NHS hospital trusts, with the median number per hospital of two patients (interquartile range (IQR) 1.0 to 5.5) over the ascertainment period. Two children (three hips) were excluded from follow-up analyses as the baseline case report forms were not completed beyond initial patient confirmation. Surgeon-reported outcomes were available in 348 of 393 hips (88.5%) at two years.
Disease frequency
The annual incidence of Perthes’ disease was 2.48 (95% CI 2.20 to 2.76) per 100,000 zero- to 14-year-olds. There was some regional variation in incidence rates, with the highest number of patients in Northern England (Table I). A complete breakdown of the epidemiology and cohort characteristics is available in the Supplementary Material.
Table I.
Annual incidence per 100,000 population of first presentation of Perthes’ disease.
| Variable | Population, n* | First presentation | |
|---|---|---|---|
| n | Incidence (95% CI) | ||
| All | 11,311,227 | 304 | 2.48 (2.20 to 2.76) |
| Region | |||
| England | 9,927,566 | 262 | 2.44 (2.14 to 2.73) |
| London/surrounding boroughs | 2,323,067 | 38 | 1.51 (1.07 to 2.07) |
| South | 1,982,386 | 63 | 2.93 (2.25 to 3.75) |
| North | 2,698,410 | 101 | 3.46 (2.78 to 4.13) |
| Central | 2,923,703 | 60 | 1.89 (1.45 to 2.44) |
| Wales | 523,183 | 16 | 2.82 (1.61 to 4.58) |
| Scotland | 860,478 | 26 | 2.79 (1.82 to 4.09) |
| Age group | |||
| 0 to 5 yrs | 4,692,365 | 166 | 3.27 (2.88 to 3.76) |
| 6 to 10 yrs | 3,850,071 | 117 | 2.81 (2.30 to 3.31) |
| 11 to 14 yrs | 2,768,791 | 21 | 0.7 (0.43 to 1.07) |
| Sex | |||
| Male | 5,793,959 | 231 | 3.68 (3.21 to 4.15) |
| Female | 5,517,268 | 71 | 1.22 (0.96 to 1.54) |
-
*
Zero- to 14-year-olds in England, Scotland, and Wales (2016 mid-year estimate from the Office for National Statistics).26
-
CI, confidence interval.
Cohort characteristics
The median age of the cohort was 5.4 years (IQR 4.2 to 7.4), with a strong preponderance in males (288 male (77.6%) vs 83 female (22.4%)). The ethnicity was ‘White British’ in 90.6% of patients. Among those for whom the family history was known (346 of 371 children), 20 (5.8%) had a first-degree relative affected by Perthes’ disease.
Disease characteristics
Of the patients, 346 (93.3%) had new unilateral disease, and 25 (6.7%) had new bilateral disease. In total, 396 hips were newly diagnosed within the timeframe of the study. At inclusion, 154 hips (40.7%) were described by clinicians to have significantly limited abduction (i.e. stiffness). The radiological appearance at inclusion was Waldenström stage 2A (early fragmentation) or earlier in 301 hips (77.2%; Table II), with 262 (66.8%) having no collapse or under 50% collapse of the lateral column. The involvement of disease on the lateral radiograph was available in 249 hips (67.1%), with 154 (61.8%) reporting > 50% head involvement.
Table II.
Stage and severity of Perthes’ disease at diagnosis.
| Variable | Total |
|---|---|
| Newly affected hips, n (%) | |
| Total | 396 (100) |
| Unilateral | 346 (93.3) |
| Bilateral | 25 (6.7) |
| Documented stiffness, n (%) | |
| Stiff | 145 (40.7) |
| Minimal/no stiffness | 224 (59.3) |
| Missing | 18 |
| Waldenström classification, n (%) | |
| 0 | 11 (2.8) |
| 1A | 63 (16.2) |
| 1B | 134 (34.4) |
| 2A | 93 (23.8) |
| 2B | 51 (13.1) |
| 3A | 16 (4.1) |
| 3B | 15 (3.8) |
| 4 | 7 (1.8) |
| Missing | 6 |
| Collapse of lateral column on AP radiograph, n (%) | |
| No collapse | 104 (29.5) |
| < 50% | 158 (44.8) |
| Exactly 50% | 29 (8.2) |
| > 50% | 62 (17.6) |
| Missing | 4 |
| Head involvement on lateral radiograph, n (%)† | |
| > 50% of head involvement | 154 (61.8) |
| < 50% of head involvement | 95 (38.2) |
| Missing | 0 |
-
*
Anteroposterior radiographs available for 357 hips.
-
†
Lateral radiographs available for 249 hips.
-
AP, anteroposterior.
Equipoise and decision-making
At the point of entry into the study, there was a strategy in place for treating 249 (65.0%) hips, with 67 (26.9%) planned for surgical treatment and 182 (73.1%) planned for non-surgical treatment. We hypothesized that an age cut-off of six years, hip stiffness, and the amount of femoral head involvement would be the main predictors of whether a child was planned to receive surgery (Figure 1a). However, an optimized decision tree, generated through recursive partitioning, demonstrated stiffness as the most important predictor of surgery, and an age cut-off at eight years as the next most important predictor (Figure 1b). At inclusion into the cohort, 129 (93%) hips without stiffness were planned for nonoperative treatment versus 49 (46%) of those described to have stiffness.
Fig. 1
Likelihood of a surgical versus non-surgical strategy according to an a) a priori constructed decision tree and b) optimized decision tree using recursive partitioning to best fit the data, which included optimizing the cut-off for age, based on the 249 hips with a treatment strategy in place at baseline. AP, anteroposterior.
Over the course of follow-up, many more children underwent surgery as treatment strategies evolved. In total, 117 (33.4%) hips were treated surgically, and 233 (66.6%) treated non-surgically. The treatment details of 46 hips were unknown.
Technical intervention variables
Of the 233 hips definitively treated nonoperatively over the two-year follow-up period, management involved observation alone in 207 hips (88.9%), with nonoperative interventions in 23 hips. Of the nonoperative interventions, 19 hips (8.3%) were advised to prevent weightbearing through the affected leg and four (1.7%) were treated in a hip spica/orthosis, with restrictions lasting for a median of 50 weeks (IQR 26 to 52).
Of the 117 hips definitively treated with surgery over the two-year follow-up period, this involved surgery to the bone in 111 (96.5%). Bone surgery most frequently concerned a ‘containment’ osteotomy: varus osteotomy (n = 63; 57.8%), shelf osteotomy (n = 35; 32.1%), Salter osteotomy (n = 5; 4.5%), and other redirectional acetabular osteotomy (n = 2; 1.8%). Other bone surgery included core decompression (n = 1; 0.9%) and hip distraction (n = 2; 1.8%), with four missing or unspecified. Soft-tissue surgery (with/without bone surgery) was undertaken in 41 of those undergoing surgery (35%), with adductor release and psoas release commonly performed.
Physiotherapy was recommended in 207 (61.2%) children. Other therapies were rare, and included botulinum toxin (n = 1), steroids (n = 4), and treatment with vitamin D (n = 5).
Surgeon-reported outcomes
At inclusion into the cohort, 300 hips (79.1%) were described to be in early fragmentation or earlier in the disease process. At the two-year follow-up visit, 299 hips (92.0%) available for follow-up were in early reossification or later (Table III).
Table III.
Radiological stage of hips at each follow-up timepoint.
| Waldenström classification | Baseline, n | 1 yr, n | 2 yrs, n |
|---|---|---|---|
| 0 | 11 | 7 | 8 |
| 1 A | 63 | 6 | 3 |
| 1B | 113 | 13 | 4 |
| 2A | 93 | 30 | 4 |
| 2B | 51 | 80 | 7 |
| 3A | 14 | 127 | 72 |
| 3B | 13 | 59 | 158 |
| 4 | 1 | 17 | 69 |
Overall, 227 hips (69.8%) were in late reossification or the healed stage, which was the point at which an assessment of hip shape was permitted. Of these, 39 (17.5%) were Stulberg 1 (17.5%), 59 Stulberg 2 (26.5%), 84 Stulberg 3 (37.7%), 26 Stulberg 4 (11.7%), and 15 Stulberg 5 (6.7%). A total of 141 radiographs were available to the study team. The quantifiable measure of hip shape (AP roundness error) was associated with Stulberg grades reported by reporting clinicians (Figure 2).
Fig. 2
Anteroposterior (AP) roundness error stratified by two-year Stulberg grade. This was restricted to hips that reached modified Waldenström stage 3B or 4.
Ordinal regression suggests that age and sex were the only baseline factors associated with two-year Stulberg grade, with the degree of lateral pillar collapse near to statistical significance: children aged six years or more at baseline, and/or female, and/or > 50% lateral column collapse were more likely to have a worse outcome at two years. Most importantly, neither clinical stiffness nor surgical treatment on the hip appeared to have any bearing on outcome (Table IV).
Table IV.
Multivariable ordinal regression model fitting Stulberg grade at two years with respect to baseline covariates.
| Variable | Proportional adjusted OR (95% CI) | p-value |
|---|---|---|
| Sex | 0.012 | |
| Male | 1.00 (reference) | |
| Female | 2.27 (1.19 to 4.34) | |
| Age at entry | 0.007 | |
| < 6 yrs | 1.00 (reference) | |
| ≥ 6 yrs | 2.62 (1.30 to 5.28) | |
| Stiffness* | 0.656 | |
| None/minimal | 1.00 (reference) | |
| Stiff hip | 1.16 (0.61 to 2.20) | |
| Head involvement (lateral pillar collapse) | 0.052 | |
| < 50% | 1.00 (reference) | |
| ≥ 50% | 2.19 (0.99 to 4.83) | |
| Surgical treatment | 0.923 | |
| No surgery | 1.00 (reference) | |
| Surgery | 1.03 (0.55 to 1.96) |
-
*
Stiffness of hip was added to this analysis post hoc.
-
CI, confidence interval; OR, odds ratio.
Patient-reported outcomes
In total, 57 of the 144 sites agreed to invite participants to complete patient-reported outcomes, and 172 participants were enrolled to provide PROMs. At baseline, 82 children were recruited with a completion rate of 85% (70/85). However, at one year and two years, completion rates were only 27% (41/150) and 58% (99/172) from 150 and 172 children, respectively. Those completing PROMs were broadly representative of the surveillance cohort in terms of age at diagnosis, sex, ethnicity, and BMI. Figure 3 illustrates the impact of the disease on the child using the PedsQL subdomains. Univariate analysis was unable to demonstrate any significant association between baseline characteristics (i.e. age, sex, BMI, stiffness, collapse, lateral head involvement, treatment, and centre-volume) and any of the recorded PROMs (i.e. EQ-5D-Y, PedsQL, or Wong Baker). See Supplementary Material for a complete breakdown of the outcome data.
Fig. 3
Distribution of Paediatric Quality of Life Inventory scores in Perthes’ disease patients at a) baseline (n = 70) and b) two years (n = 99), based on established categorizations.
Complications
Complications of treatment, either with surgery or without surgery, were rare. There were no periprosthetic fractures associated with the surgical osteotomies. The only unplanned surgical complication was a pin exchange related to an external fixator. Within the follow-up period, 48 hips had additional surgery after their initial treatment intervention, and 26 were planned to subsequently undergo surgery. Additionally, 40 hips had undergone removal of metal hardware, with a further 14 hips scheduled to undergo removal. One patient underwent arthroplasty surgery within the follow-up period, and four were scheduled to undergo arthroplasty surgery.
Non-containment surgery completed and planned included epiphysidodesis for leg length inequality (n = 5), ablation of the greater trochanter apophysis (n = 2), realignment ostoeotomies for impingement (i.e. valgus osteotomy; n = 6), soft-tissue surgery (n = 2), femoral head decompression (n = 1), shelf osteotomy (n = 1), and osteochondroplasty for impingement (n = 1).
Seven opposite (contralateral) hips were affected by Perthes’ disease during the two-year follow-up period. The risk of contralateral disease during the two years after being diagnosed with unilateral disease was 2.1% (95% CI 0.6% to 3.6%). Given the low event rate, it was not possible to investigate the effect of baseline factors on this outcome.
Discussion
There is widespread variation in the approaches to treatment of Perthes’ disease of the hip in children in the UK. The key uncertainty appears to be the effectiveness of ‘containment surgery’ in treating the disease. While we were able to identify the importance of known prognostic factors, we were unable to demonstrate that stiffness was an important prognostic factor, and moreover were unable to demonstrate any benefit from surgery to contain the hip.
At presentation, the strategy for the decision to offer surgery appeared to be principally based on the clinical stiffness of the hip and the age of the child. The optimized prediction algorithm demonstrated that surgeons typically used the age of eight years as a decision cut-off when planning treatment, which was different to the our hypothesized decision cut-off of six years. Treatment strategies often evolved over the course of the study, with one-quarter initially planned for surgery, yet over one-third ultimately undergoing surgery.
This is the first study to measure PROMs to demonstrate the severe impact of the disease on the child. There was a marked effect on the life of the child at diagnosis, with many aspects of health being significantly impacted even after two years. The domain of physical function was most influenced by the disease, with a marked improvement at final follow-up. However, even after two years, and despite the evident improvement in outcomes, the PedsQL scores are sufficiently impacted to be indicative of an ongoing ‘major chronic condition’, using established cut-offs of PedsQL.27 Notwithstanding the potential for bias among responders, there are few diseases in childhood with such a profound effect on quality of life over such a prolonged period.
The epidemiology of disease within our cohort is similar to that known, such that the disease principally affects White boys from Northern England.4,5 However, the incidence in our study is lower than that previously reported,2,5,28 and may be an underestimate of the true incidence, or may reflect a decline in frequency which has been previously observed.5
There are only two prior multicentre prospective studies of Perthes’ disease.9,10 Each concluded that surgery had a small positive influence on Perthes’ disease in specific subgroups of patients. However, each of these studies relied on post-hoc analyses, and are therefore at risk of type I error through multiple hypothesis testing and identifying subgroups through novel positive findings. We did not reproduce their findings of a positive effect of surgery, though we were able to confirm other known prognostic factors had an influence on the radiological outcome; namely age, sex, and radiological evidence of femoral head collapse.29
The impact of Perthes’ disease on the child has not previously been well explored. A qualitative study of children and their families explored the effects of the disease on the life of the child and wider family, identifying a range of areas of life impacted by this illness.30 A disease-specific core outcome set has now been formulated, which is a group of outcomes important to measure in all high-quality studies, which should usefully guide outcome choices in future research in Perthes' disease.31
While the BOSS study used comprehensive methods to maximize patient verification, Perthes’ disease was often managed in an outpatient setting. When investigating slipped capital femoral epiphysis, the BOSS study was able to use inpatient administrative data to identify missed cases of the disease, which was not possible in Perthes’ disease. The use of a trainee network to optimize case ascertainment, while helpful, is likely to miss patients with a childhood chronic disease, as surgical trainees are less involved in the care of these patients than other areas such as trauma. The case identification within our cohort may therefore under-represent the true incidence of Perthes’ disease in the UK.
Within the study, the radiological outcomes were determined at two years among those in the late reossification or healed stage of disease. Prior studies have demonstrated that hip shape can be reliably determined at healing, rather than waiting until skeletal maturity.32 However, only 227 hips (70.9%) were sufficiently mature to assign a radiological outcome at this stage. While this is unlikely to introduce bias, the missing data points do introduce uncertainties with the estimates of effect size.
PROMs at later timepoints were poorly collected within the study. Low completion rates made interpretation of the outcomes by treatment group difficult, as the study was underpowered to identify differences. We also acknowledge the potential for non-responder bias in the completion of PROMs. Nevertheless, the outcomes clearly identified the profound impact of the disease on the child. The low completion rate of PROMs probably reflected the immaturity of the national collaborative, with no previous successful prospective research in paediatric orthopaedic surgery prior to this BOSS study.
This study strengthens the argument for a definitive RCT by demonstrating sufficient numbers in the UK, revealing the far-reaching effect of the disease on the child and highlighting the uncertainties in surgical care. The definitive trial should consider incorporating several elements evident from this feasibility study. Physical function should be considered a candidate for the primary outcome, as the disease had most impact on the domain of physical function. Follow-up should be greater than two years, to enable sufficient time to ensure that the hip shape of participants can be reliably classified, and age, sex, and radiological severity should be carefully considered in the design and analysis, given the known association with outcome.
In conclusion, we have demonstrated that Perthes’ disease has a marked effect on the quality of life of children over a prolonged period. We have also shown that currently there is a widespread variation in surgical care, with significant uncertainties about the optimal treatment strategy. However, we did not find any evidence to support the view that there were improved outcomes among those undergoing surgical treatment. Therefore there is a clear need to address the question of surgery through a RCT, which now appears feasible within the context of the UK research network that has developed through the delivery of this study.
References
1. Perry DC , Skellorn PJ , Bruce CE . The lognormal age of onset distribution in Perthes’ disease: an analysis from a large well-defined cohort . Bone Joint J . 2016 ; 98-B ( 5 ): 710 – 714 . Crossref Google Scholar
2. Perry DC , Bruce CE , Pope D , Dangerfield P , Platt MJ , Hall AJ . Perthes’ disease: deprivation and decline . Arch Dis Child . 2011 ; 96 ( 12 ): 1124 – 1128 . Crossref Google Scholar
3. Metcalfe D , Peterson N , Wilkinson JM , Perry DC . Temporal trends and survivorship of total hip arthroplasty in very young patients: a study using the National Joint Registry data set . Bone Joint J . 2018 ; 100-B ( 10 ): 1320 – 1329 . Crossref PubMed Google Scholar
4. Perry DC , Machin DMG , Pope D , et al. Racial and geographic factors in the incidence of Legg-Calvé-Perthes’ disease: a systematic review . Am J Epidemiol . 2012 ; 175 ( 3 ): 159 – 166 . Crossref Google Scholar
5. Perry DC , Bruce CE , Pope D , Dangerfield P , Platt MJ , Hall AJ . Legg-Calvé-Perthes disease in the UK: geographic and temporal trends in incidence reflecting differences in degree of deprivation in childhood . Arthritis Rheum . 2012 ; 64 ( 5 ): 1673 – 1679 . Crossref PubMed Google Scholar
6. Perry DC , Bruce CE , Pope D , Dangerfield P , Platt MJ , Hall AJ . Perthes’ disease of the hip: socioeconomic inequalities and the urban environment . Arch Dis Child . 2012 ; 97 ( 12 ): 1053 – 1057 . Crossref Google Scholar
7. Galloway AM , Holton C , Parnami V , et al. A case review to describe variation in care following diagnosis of Perthes’ disease . Bone Jt Open . 2020 ; 1 ( 11 ): 691 – 695 . Crossref Google Scholar
8. Galloway AM , van-Hille T , Perry DC , et al. A systematic review of the non-surgical treatment of Perthes’ disease . Bone Jt Open . 2020 ; 1 ( 12 ): 720 – 730 . Crossref Google Scholar
9. Wiig O , Terjesen T , Svenningsen S . Prognostic factors and outcome of treatment in Perthes’ disease: a prospective study of 368 patients with five-year follow-up . J Bone Joint Surg Br . 2008 ; 90-B ( 10 ): 1364 – 1371 . Crossref Google Scholar
10. Herring JA , Kim HT , Browne R . Legg-Calve-Perthes disease. Part II: Prospective multicenter study of the effect of treatment on outcome . J Bone Joint Surg Am . 2004 ; 86-A ( 10 ): 2121 – 2134 . Crossref PubMed Google Scholar
11. Perry DC , Wright JG , Cooke S , et al. A consensus exercise identifying priorities for research into clinical effectiveness among children’s orthopaedic surgeons in the United Kingdom . Bone Joint J . 2018 ; 100-B ( 5 ): 680 – 684 . Crossref Google Scholar
12. Vella-Baldacchino M , Perry DC , Roposch A , et al. Research priorities in children requiring elective surgery for conditions affecting the lower limbs: a James Lind Alliance Priority Setting Partnership . BMJ Open . 2019 ; 9 ( 12 ): e033233 . Crossref PubMed Google Scholar
13. McCulloch P , Cook JA , Altman DG , Heneghan C , Diener MK , IDEAL Group . IDEAL framework for surgical innovation 1: the idea and development stages . BMJ . 2013 ; 346 : f3012 . Crossref PubMed Google Scholar
14. Ergina PL , Barkun JS , McCulloch P , Cook JA , Altman DG , IDEAL Group . IDEAL framework for surgical innovation 2: observational studies in the exploration and assessment stages . BMJ . 2013 ; 346 : f3011 . Crossref PubMed Google Scholar
15. Cook JA , McCulloch P , Blazeby JM , et al. IDEAL framework for surgical innovation 3: randomised controlled trials in the assessment stage and evaluations in the long term study stage . BMJ . 2013 ; 346 : f2820 . Crossref PubMed Google Scholar
16. Perry DC , Arch B , Appelbe D , Francis P , Spowart C , Knight M . The BOSS Study. Determining the incidence and clinical outcomes of uncommon conditions and events in orthopaedic surgery . Bone Jt Open . 2020 ; 1 ( 3 ): 41 – 46 . Crossref PubMed Google Scholar
17. Varni JW , Seid M , Kurtin PS . PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations . Med Care . 2001 ; 39 ( 8 ): 800 – 812 . Crossref PubMed Google Scholar
18. Eidt-Koch D , Mittendorf T , Greiner W . Cross-sectional validity of the EQ-5D-Y as a generic health outcome instrument in children and adolescents with cystic fibrosis in Germany . BMC Pediatr . 2009 ; 9 : 55 . Crossref PubMed Google Scholar
19. Wong DL , Baker CM . Pain in children: comparison of assessment scales . Pediatr Nurs . 1988 ; 14 ( 1 ): 9 – 17 . PubMed Google Scholar
20. Bilbro NA , Hirst A , Paez A , et al. The IDEAL reporting guidelines: a Delphi consensus statement stage specific recommendations for reporting the evaluation of surgical innovation . Ann Surg . 2021 ; 273 ( 1 ): 82 – 85 . Crossref PubMed Google Scholar
21. Herring JA , Kim HT , Browne R . Legg-Calve-Perthes disease. Part I: Classification of radiographs with use of the modified lateral pillar and Stulberg classifications . J Bone Joint Surg Am . 2004 ; 86-A ( 10 ): 2103 – 2120 . Crossref PubMed Google Scholar
22. Salter RB , Thompson GH . Legg-Calvé-Perthes disease. The prognostic significance of the subchondral fracture and a two-group classification of the femoral head involvement . J Bone Joint Surg Am . 1984 ; 66-A ( 4 ): 479 – 489 . Crossref PubMed Google Scholar
23. Hyman JE , Trupia EP , Wright ML , et al. Interobserver and intraobserver reliability of the modified Waldenström classification system for staging of Legg-Calvé-Perthes disease . J Bone Joint Surg Am . 2015 ; 97-A ( 8 ): 643 – 650 . Crossref PubMed Google Scholar
24. Neyt JG , Weinstein SL , Spratt KF , et al. Stulberg classification system for evaluation of Legg-Calvé-Perthes Disease . J Bone Joint Surg Am . 1999 ; 81-A ( 9 ): 1209 – 1216 . Crossref PubMed Google Scholar
25. Shah H , Siddesh ND , Pai H , Tercier S , Joseph B . Quantitative measures for evaluating the radiographic outcome of Legg-Calvé-Perthes disease . J Bone Joint Surg Am . 2013 ; 95-A ( 4 ): 354 – 361 . Crossref PubMed Google Scholar
26. No authors listed . Population estimates for the UK, England and Wales, Scotland and Northern Ireland: mid-2016 Office for National Statistics . 2017 . https://www.ons.gov.uk/peoplepopulationandcommunity/populationandmigration/populationestimates/bulletins/annualmidyearpopulationestimates/mid2016 ( date last accessed 25 February 2022 ). Google Scholar
27. Rosenberg AR , Orellana L , Ullrich C , et al. Quality of life in children with advanced cancer: a report from the PediQUEST study . J Pain Symptom Manage . 2016 ; 52 ( 2 ): 243 – 253 . Crossref PubMed Google Scholar
28. Margetts BM , Perry CA , Taylor JF , Dangerfield PH . The incidence and distribution of Legg-Calvé-Perthes’ disease in Liverpool, 1982-95 . Arch Dis Child . 2001 ; 84 ( 4 ): 351 – 354 . Crossref Google Scholar
29. Catterall A . Perthes’s disease . Br Med J . 1977 ; 1 ( 6069 ): 1145 – 1149 . Crossref Google Scholar
30. Leo DG , Murphy R , Gambling T , Long A , Jones H , Perry DC . Perspectives on the social, physical, and emotional impact of living with perthes’ disease in children and their family: a mixed methods study . Glob Pediatr Health . 2019 ; 6 : 2333794X19835235 . Crossref Google Scholar
31. Leo DG , Jones H , Murphy R , et al. The outcomes of perthes’ disease: development of a core outcomes set for clinical trials in perthes’ disease . Bone Joint J . 2020 ; 102-B : 611 – 617 . Crossref Google Scholar
32. Siddesh ND , Shah H , Tercier S , Pai H , Nair S , Joseph B . The sphericity deviation score: a quantitative radiologic outcome measure of Legg-Calvé Perthes disease applicable at the stage of healing and at skeletal maturity . J Pediatr Orthop . 2014 ; 34 ( 5 ): 522 – 528 . Crossref PubMed Google Scholar
Author contributions
D. C. Perry: Conceptualization, Methodology, Funding acquisition, Project administration, Resources, Software, Supervision, Investigation, Data curation, Formal analysis, Validation, Visualization, Writing – original draft, Writing – review & editing.
B. Arch: Methodology, Formal analysis, Validation, Writing – review & editing.
D. Appelbe: Methodology, Software, Investigation, Writing – review & editing.
P. Francis: Project administration, Data curation.
J. Craven: Project administration, Writing – review & editing
F. P. Monsell: Conceptualization, Supervision, Writing – review & editing.
P. Williamson: Methodology, Formal analysis, Writing – review & editing.
M. Knight: Conceptualization, Methodology, Supervision, Writing – original draft.
Funding statement
The authors disclose receipt of the following financial or material support for the research, authorship, and/or publication of this article: independent research funded by the National Institute for Health Research (NIHR) through a NIHR Clinician Scientist Fellowship (CS-2014-14-012) awarded to D. C. Perry. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The Alder Hey Charity also financially contributed to this work.
Acknowledgements
We would like to thank all those involved in making BOSS a success, including the patients and their parents/carers, the research associates at all the research sites, the multidisciplinary teams including nurses, radiographers, physiotherapists and orthopaedic surgeons from different hospitals in the UK. Thanks to the BOSS steering committee which included Prof. Xavier Griffin (Barts Health NHS Trust), Prof. Mike Pearson (University of Liverpool), Emma Morely (Patient representative, STEPS charity) and was chaired by Prof. James Wright (Hospital for Sick Children, Toronto). Further thanks to Jenny Preston for her facilitation of patient and public engagement and the children and young people of the Generation R Liverpool Young Person’s Advisory Group (YPAG). In particular, we would like to thank Cath Spowart and Emma Cwiklinski for their commitment in trial coordination and management.
Thank you to the individuals who led data collection at each site:
A. Kitching, Airedale NHS Foundation Trust; C. Bruce, Alder Hey Children's NHS FoundationTrust; S. Lewis, Aneurin Bevan University Health Board; K. Vemulapalli and A. Acharya, Barking, Havering and Redbridge University Hospitals NHS Trust; S. Sharma, Barnsley Hospital NHS Foundation Trust; M. Ramachandran, Barts Health NHS Trust; M. Tiruveedhula and S. Symons, Basildon & Thurrock University Hospital NHS Foundation Trust; P. Edge, Bedfordshire Hospitals NHS Foundation Trust; K. Azurza and D. A. V. O'Kelly, Betsi Cadwaladr University Health Board; E. Bache, Birmingham Women's and Children's NHS Foundation Trust; A. Anand, Blackpool Teaching Hospitals NHS Foundation Trust; S. Livingston, Borders General Hospital; D. Shaw, Bradford Teaching Hospitals NHS Foundation Trust; S. N. Maripuri, Brighton and Sussex University Hospitals NHS Trust; J. Hicks, Buckinghahire Healthcare NHS Trust; S. Burgess, Calderdale and Huddersfield NHS Foundation Trust; K. Stohr and A. Rehm, Cambridge University Hospitals NHS Foundation Trust; C. Carpenter and P. Thomas, Cardiff and Vale University Local Health Board; S. Evans, Chelsea and Westminster Hospital NHS Foundation Trust; J. Cashman, Chesterfield Royal Hospital NHS Foundation Trust; G. DeKiewiet and I. Talkhani, City Hospitals Sunderland NHS Foundation Trust; V. S. Shanker and V. Mula, Colchester Hospital University NHS Foundation Trust; K. Thomason and M. Nixon, Countess of Chester Hospital NHS Foundation Trust; J. Page, County Durham and Darlington NHS Foundation Trust; J. Murray, Cwm Taf Health Board; M. Mohan Utukuri and S. Tafazal, Derby Hospitals NHS Foundation Trust; R. Kucharski and S. Madan, Doncaster and Bassetlaw Hospitals NHS Foundation Trust; N. Savva, Dorset County Hospital NHS Foundation Trust; A. Hawkins, Dumfries and Galloway Royal Infirmary; N. De Roeck, East and North Hertfordshire NHS Trust; M. Cornell, East Kent Hospitals University NHS Foundation Trust; R. Paton, East Lancashire Hospitals NHS Trust; A. Butler-Manuel, East Sussex Healthcare NHS Trust; E. Oakley, Epsom and St Helier University Hospitals NHS Trust; F. Norman-Taylor, Evelina London Children’s Hospital; B. Murray, Forth Valley Royal Hospital; A. Jalgaonkar and T. Jacob, Frimley Park Hospital NHS Foundation Trust; D. Rowland, Glasgow Royal Infirmary; M. Henderson, Gloucestershire Hospitals NHS Foundation Trust; A. Roposch and Y. Jabbar, Great Ormond Street Hospital for Children NHS Foundation Trust; S. Irby, Great Western Hospitals NHS Foundation Trust; M. Kokkinakis and D. Reed, Guys and St Thomas NHS Foundation Trust; I. Macleod and N. Rossiter and K. Conn, Hampshire Hospitals NHS Foundation Trust; D. Lavalette, Harrogate and District NHS Foundation Trust; R. Dimitriou, Heart Of England NHS Foundation Trust; H. Bhatt, Hillingdon Hospitals NHS Foundation Trust; A. Patel and S. Jiwanmall, Hinchingbrooke Health Care NHS Trust; T. Baring, Homerton University Hospital NHS Foundation Trust; S. Hobson and E. Moulder, Hull University Teaching Hospitals NHS Trust; R. Bhattacharya and K. Sarraf, Imperial College Healthcare NHS Trust; D. Donaldson, Inverclyde Royal Hospital; G. Carlile, Ipswich Hospital NHS Trust; S. Shyamsundar and S. Siddiqui, Kettering General Hospital NHS Foundation Trust; O. Lahoti and I. Reichert, Kings College Hospital NHS Foundation Trust; T. McEvoy and P. Kasliwal, Lancashire Teaching Hospitals NHS Foundation Trust; C. Holton, Leeds Teaching Hospitals NHS Trust; M. Abdus-Samee and S. Bajaj, Lewisham and Greenwich NHS Trust; S. Verma, Luton and Dunstable Hospital NHS Foundation Trust; M. Katchburian, J. Dartnell, Maidstone and Tunbridge Wells NHS Trust; M. Kenawey, Manchester University NHS Foundation Trust (Manchester Children's Hospital); B. Singh and M. Bhat, Medway NHS Foundation Trust; D. Machin and H. Kazi, Mid Cheshire Hospitals NHS Foundation Trust; P. Buddhdev and J. Tuite, Mid Essex Hospital Services NHS Trust; N. Tulwa, Mid Yorkshire Hospitals NHS Trust; J. Flynn and M. Khalik, Milton Keynes Hospital NHS Foundation Trust; D. Campbell and J. MacLean, NHS Tayside; A. P. Sanghrajka and R. Hutchinson, Norfolk and Norwich University Hospitals NHS Foundation Trust; C. Brignall, North Cumbria University Hospitals NHS Trust; V. Asopa, North Middlesex University Hospital NHS Trust; I. Holloway, North West London Hospitals NHS Trust; R. Natarajan and K. Muthusamy, Northampton General Hospital NHS Trust; L. Brunton, Northern Devon Healthcare NHS Trust; F. Howell, Northern Lincolnshire and Goole Hospitals NHS Foundation Trust; M. Reed and R. Critchley, Northumbria Healthcare NHS Foundation Trust; K. Price and J. Hunter, Nottingham University Hospitals NHS Trust; R. Buckingham and A. Wainwright, Oxford University Hospitals NHS Trust; A. Bonshahi and E. Yates, Pennine Acute Hospitals NHS Trust; P. Mitchell, Peterborough and Stamford Hospitals NHS Foundation Trust; B. Holroyd and J. Aird, Plymouth Hospitals NHS Trust; R. Richards, Portsmouth Hospitals University NHS Trust; P. Renshaw and K. Mcleod, Raigmore Hospital; R. Freeman, Robert Jones and Agnes Hunt Orthopaedic and District Hospital NHS Trust; S. Barker and L. Mills, Royal Aberdeen Children’s Hospital; R. B Abu-Rajab and J. Smith, Royal Alexandria Hospital; N. Davies, Royal Berkshire NHS Foundation Trust; R. Hawkins, Royal Cornwall Hospitals NHS Trust; P. Cox and J. Howell, Royal Devon and Exeter NHS Foundation Trust; O. Malaga Shaw, Royal Free London NHS Foundation Trust; J. Saksena, Royal Free London NHS Foundation Trust (Barnet and Chase Farm Hospitals); E. Baird and M. Gaston, Royal Hospital for Sick Children, Edinburgh; N. Wilson, Royal Hospital for Sick Children, Glasgow; D. Eastwood and A. Hashemi-Nejad, Royal National Orthopaedic Hospital NHS Trust; C. Coates, Royal Surrey County NHS Foundation Trust; A. McBride, Royal United Hospital Bath NHS Trust; P. Pettit, Salisbury NHS Foundation Trust; S. Roy, Sandwell and West Birmingham Hospitals NHS Trust; S. Joshy, Scarborough and North East Yorkshire Health Care NHS Trust; N. Nicolaou and S. Madan, Sheffield Children’s NHS Foundation Trust; J. Rhee, Shrewsbury and Telford Hospital NHS Trust; G. Wansbrough, South Devon Healthcare NHS Foundation Trust; R. Tate and D. Ferguson, South Tees Hospitals NHS Foundation Trust; H. Mackay, Southport and Orkirk Hospital NHS Trust; K. Dal, Y. Gelfer, and A. Yeo, St Georges Healthcare NHS Trust; S. Lipscombe, St Helens and Knowsley Hospitals NHS Trust; B. Morgan and S. Alshryda, Stockport NHS Foundation Trust; P. Williams, Swansea Bay University Health Board; W. Jamil, Tameside Hospital NHS Foundation Trust; A. Kelly and E. Mounsey, Taunton and Somerset NHS Foundation Trust; V. Spiteri, The Dudley Group NHS Foundation Trust; P. Henman, W. Bliss, and A. de Gheldere, The Newcastle Upon Tyne Hospitals NHS Foundation Trust; D. Manoukian, The Princess Alexandra Hospital NHS Trust; S. Giles and S. Weston-Simons, The Rotherham NHS Foundation Trust; R. Vadivelu, The Royal Wolverhampton NHS Trust; A. O'Gorman and C. Charalambides, The Whittington Hospital NHS Trust; I. Majid, The Bolton NHS Foundation Trust; R. Hopcroft, The James Cook University Hospital; T. Southorn and R. Asirvatham, United Lincolnshire Hospitals NHS Trust; M. Oddy and J. Witt, University College London Hospitals NHS Foundation Trust; R. Marian Short and M. Zgoda, University Hospital Crosshouse; N. Kurdy, University Hospital of South Manchester NHS Foundation Trust; A. Aarvold, M. Uglow, and K. Elliott, University Hospital Southampton NHS Foundation Trust; F. Monsell, S. Thompson, and G. Atherton, University Hospitals Bristol NHS Foundation Trust; S. Cooke and G. Pattison, University Hospitals Coventry and Warwickshire NHS Trust; A. Abraham and A. Kulkarni, University Hospitals of Leicester NHS Trust; K. Allison, University Hospitals of Morecambe Bay NHS Foundation Trust; B. Carsi, University Hospitals of the North Midlands; K. Periasamy, University Hospital Hairmyres; A. Murray and K. Ferguson, University Hospital Monklands; N. Marriott, Warrington and Halton Hospitals NHS Foundation Trust; K. Deierl, West Hertfordshire Hospitals NHS Trust; V. Babu and H. Zadeh, West Middlesex University Hospital NHS Trust; S. Deakin, West Suffolk NHS Foundation Trust; A. Predl, Western Isles Hospital; K. Sri-Ram, Whipps Cross University Hospital; G. Jackson, Wirral University Teaching Hospital NHS Foundation Trust; C. Docker, Worcestershire Acute Hospitals NHS Trust; A. Ajis, Worthing And Southlands Hospitals NHS Trust; H. Wynn-Jones, H. Divecha, and B. D. Coupe, Wrightington, Wigan and Leigh NHS Foundation Trust; I. Bissell, Wye Valley NHS Trust; and S. Hobson, York Teaching Hospital NHS Foundation Trust.
Thank you to the trainees who submitted data. The following trainees reliably submitted data for at least four consecutive months during the project:
A. Dick, A. J Grazette, A. Doorgakant, B. A. Marson, C. E. Hill, D. Shields, D. Hansom, I. McLaughlin-Simon, J. T. Bourne, L. H. Lee, M. Hughes, M. Mohamed, M. A. Akhtar, mnN. M. Ormsby, P. Buddhev, R. Gogna, R. J. Critchley, R. W. D. Pilling, T. Boutefnouchet, T. Wood, W. D. Harrison, M. Chamberlain, Z. Hashim, E. Davidson, and T. Koc.
Ethical review statement
This programme of work complies with the Declaration of Helsinki and was reviewed and approved by the National Research Ethics Service Committee London – City and East (REC ref: 15/LO/2202) and the Health Research Authority (ref: 190754).
Open access funding
Open access funding was provided by the National Institute for Health Research (NIHR) through an NIHR Clinician Scientist Fellowship (CS-2014-14-012) awarded to D. C. Perry.
Open access statement
This article is distributed under the terms of the Creative Commons Attributions (CC BY 4.0) licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original author and source are credited.
Trial registration number
The study was registered on the ISCTRN registry (ISRCTN54477575).
Follow D. C. Perry @MrDanPerry
Follow J. Craven @joanna_craven
Follow M. Knight @MarianFKnight
Follow Liverpool Clinical Trials Centre @livuni_LCTC
Follow Oxford Trauma and Emergency Care @Oxford_Trauma
Supplementary material
The full preplanned statistical analysis concerning incidence and the initial care (Part 1), and treatment and two-year outcomes (Part 2).
This article was primary edited by S. P. F. Hughes.
