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The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 1 | Pages 1 - 11
1 Jan 2011
Murray IR Amin AK White TO Robinson CM

Most proximal humeral fractures are stable injuries of the ageing population, and can be successfully treated non-operatively. The management of the smaller number of more complex displaced fractures is more controversial and new fixation techniques have greatly increased the range of fractures that may benefit from surgery.

This article explores current concepts in the classification and clinical aspects of these injuries, reviewing the indications, innovations and outcomes for the most common methods of treatment.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 12 | Pages 1670 - 1675
1 Dec 2011
Vuillermin C Rodda J Rutz E Shore BJ Smith K Graham HK

We studied the prevalence of severe crouch gait over a 15-year period in a defined population of children with spastic diplegia and Gross Motor Function Classification System levels II and III, to determine if there had been a decrease following changes to the management of equinus gait. These changes were replacing observational with three-dimensional gait analysis, replacing single level with multilevel surgery, and replacing gastrocsoleus lengthening with gastrocnemius recession. Of 464 children and adolescents with spastic diplegia who underwent three-dimensional gait analysis, 27 had severe crouch gait. Seventeen of these had been managed by isolated lengthening of the gastrocsoleus. Following changes in the management of equinus gait, the prevalence of severe crouch gait decreased from 25% and stabilised at a significantly lower rate, fluctuating between 0% and 4% annually (p < 0.001).

We conclude that severe crouch gait in this population was precipitated by isolated lengthening of the gastrocsoleus. These findings may be relevant to other surgical populations, as severe crouch gait may be a useful way to monitor the quality of the surgical management of abnormal gait in children with cerebral palsy and spastic diplegia.


The Journal of Bone & Joint Surgery British Volume
Vol. 94-B, Issue 1 | Pages 1 - 9
1 Jan 2012
Robinson CM Seah KTM Chee YH Hindle P Murray IR

Frozen shoulder is commonly encountered in general orthopaedic practice. It may arise spontaneously without an obvious predisposing cause, or be associated with a variety of local or systemic disorders. Diagnosis is based upon the recognition of the characteristic features of the pain, and selective limitation of passive external rotation. The macroscopic and histological features of the capsular contracture are well-defined, but the underlying pathological processes remain poorly understood. It may cause protracted disability, and imposes a considerable burden on health service resources. Most patients are still managed by physiotherapy in primary care, and only the more refractory cases are referred for specialist intervention. Targeted therapy is not possible and treatment remains predominantly symptomatic. However, over the last ten years, more active interventions that may shorten the clinical course, such as capsular distension arthrography and arthroscopic capsular release, have become more popular.

This review describes the clinical and pathological features of frozen shoulder. We also outline the current treatment options, review the published results and present our own treatment algorithm.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 11 | Pages 1508 - 1512
1 Nov 2011
Choi WJ Lee JW

We evaluated the incidence of heterotopic ossification following total ankle replacement to determine whether the degree of ossification was associated with the clinical outcome. We evaluated 90 ankles in 81 consecutive patients who underwent total ankle replacement, and heterotopic ossification was assessed according to proportional involvement of the ankle joint. Correlation analysis was used to investigate the association between heterotopic ossification and outcome.

No significant association was found between the formation of heterotopic ossification and the clinical outcome. The degree of heterotopic ossification in the posterior ankle joint was not significantly correlated with posterior ankle pain (p = 0.929), the American Orthopaedic Foot and Ankle Society score (p = 0.454) or range of movement (p = 0.283).

This study indicates that caution should be observed in attributing symptoms and functional limitation to the presence of heterotopic ossification in the posterior ankle joint when considering excision of heterotopic bone after total ankle replacement.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 11 | Pages 1487 - 1492
1 Nov 2011
Macheras GA Kateros K Galanakos SP Koutsostathis SD Kontou E Papadakis SA

We report the long-term results of the management of neglected chronically infected total knee replacements with a two-stage re-implantation protocol. In 18 of 34 patients (53%) a resistant organism was isolated. All cases were treated by the same surgical team in a specialist centre and had a mean follow-up of 12.1 years (10 to 14). They were evaluated clinically and radiologically using the Knee Society Score (KSS) and the American Knee Society Roentgenographic scoring system, respectively. One patient died after eight years from an unrelated cause and two were lost to follow-up. Three patients (8.8%) developed a recurrent infection for which further surgery was required. The infection was eradicated successfully in 31 patients (91.1%). There was one case of aseptic loosening after 13 years. We found a significant improvement in the KSS at final follow-up (p < 0.001).


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 10 | Pages 1308 - 1313
1 Oct 2011
Hart AJ Sabah SA Bandi AS Maggiore P Tarassoli P Sampson B A. Skinner J

Blood metal ions have been widely used to investigate metal-on-metal hip replacements, but their ability to discriminate between well-functioning and failed hips is not known. The Medicines and Healthcare products Regulatory Agency (MHRA) has suggested a cut-off level of 7 parts per billion (ppb).

We performed a pair-matched, case-control study to investigate the sensitivity and specificity of blood metal ion levels for diagnosing failure in 176 patients with a unilateral metal-on-metal hip replacement. We recruited 88 cases with a pre-revision, unexplained failed hip and an equal number of matching controls with a well-functioning hip. We investigated the 7 ppb cut-off level for the maximum of cobalt or chromium and determined optimal mathematical cut-off levels from receiver-operating characteristic curves.

The 7 ppb cut-off level for the maximum of cobalt or chromium had a specificity of 89% and sensitivity 52% for detecting a pre-operative unexplained failed metal on metal hip replacement. The optimal cut-off level for the maximum of cobalt or chromium was 4.97 ppb and had sensitivity 63% and specificity 86%.

Blood metal ions had good discriminant ability to separate failed from well-functioning hip replacements. The MHRA cut-off level of 7 ppb provides a specific test but has poor sensitivity.


The Journal of Bone & Joint Surgery British Volume
Vol. 92-B, Issue 7 | Pages 958 - 962
1 Jul 2010
Wood PLR Karski MT Watmough P

We describe the early results of a prospective study of 100 total ankle replacements (96 patients) at a single centre using the Mobility Total Ankle Replacement. At final review, six patients had died and five ankles (5%) had been revised, two by fusion and three by exchange of components. All remaining patients were reviewed at a minimum of three years. The mean follow-up was 43 months (4 to 63). The three-year survival was 97% (95% confidence interval (CI) 91 to 99). The four-year survival was 93.6% (95% CI 84.7 to 97.4). The portion of bony interface that was visible on plain radiograph was divided into 15 zones and a radiolucent line or osteolytic cavity was seen in one zone in 14 ankles. It was not seen in more than one zone. In five ankles it was > 10 mm in width.

This study suggests that the early outcome of ankle replacement is comparable to that of other total joint replacements.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 8 | Pages 1122 - 1125
1 Aug 2011
Chandrasenan J Klezl Z Bommireddy R Calthorpe D

We retrospectively reviewed the records of 16 children treated for spondylodiscitis at our hospital between 2000 and 2007. The mean follow-up was 24 months (12 to 38). There was a mean delay in diagnosis in hospital of 25 days in the ten children aged less than 24 months. At presentation only five of the 16 children presented with localising signs and symptoms. Common presenting symptoms were a refusal to walk or sit in nine children, unexplained fever in six, irritability in five, and limping in four. Plain radiography showed changes in only seven children. The ESR was the most useful investigation when following the clinical course of the disease. Positive blood cultures were obtained in seven children with Staphylococcus aureus being isolated in five. Antibiotics were used in 14 children and spinal bracing in six. Children with spondylodiscitis often present with a confusing clinical picture leading to late diagnosis.

The early use of MRI in the investigation of children with an atypical picture may avoid unnecessary delay in starting treatment and possibly prevent long-term problems. All except one of our children had made a complete clinical recovery at final follow-up. However, all six children in the > 24-month age group showed radiological evidence of degenerative changes which might cause problems in the future.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 8 | Pages 1065 - 1070
1 Aug 2011
Tanavalee A Honsawek S Rojpornpradit T Sakdinakiattikoon M Ngarmukos S

We compared inflammation in the knee after total knee replacement (TKR) for primary osteoarthritis between two groups of patients undergoing joint replacement with and without synovectomy. A total of 67 patients who underwent unilateral TKR were randomly divided into group I, TKR without synovectomy, and group II, TKR with synovectomy. Clinical outcomes, serial serum inflammatory markers (including interleukin-6 (IL-6), CRP and ESR) and the difference in temperature of the skin of the knee, compared with the contralateral side, were sequentially evaluated until 26 weeks after surgery.

Pre-operatively, there were no statistically different clinical parameters between groups I and II. At the 26-week follow-up, both groups had a similarly significantly improved American Knee Society clinical score (p < 0.001) and functional score (p < 0.001) with no differences between the groups. Similar changes in serial inflammatory markers were found in both groups, including mean peak levels of IL-6 (189 pg/ml (sd 53.4) versus 201 pg/ml (sd 49.4) for groups I and II, respectively) and CRP (91 mg/L (sd 24.1) versus 88 mg/L (sd 23.4), respectively) on the first post-operative day, returning to pre-operative values at two and six weeks, respectively. The mean peak level of ESR for the respective two groups was 46 mm/hr versus 48 mm/hr at two weeks, which had still not returned to its pre-operative mean value at 26 weeks. The elevation in the skin temperature appeared to mirror the peak elevation of the ESR, with a range of 2.5° C to 4.5° C with some reduction at 26 weeks but still exceeding the pre-operative value.

We concluded that synovectomy at the time of TKR does not provide any benefit to the clinical outcome or shorten the duration of the inflammatory response after surgery.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 8 | Pages 1134 - 1139
1 Aug 2011
Schindeler A Birke O Yu NYC Morse A Ruys A Baldock PA Little DG

Congenital pseudarthrosis of the tibia is an uncommon manifestation of neurofibromatosis type 1 (NF1), but one that remains difficult to treat due to anabolic deficiency and catabolic excess. Bone grafting and more recently recombinant human bone morphogenetic proteins (rhBMPs) have been identified as pro-anabolic stimuli with the potential to improve the outcome after surgery. As an additional pharmaceutical intervention, we describe the combined use of rhBMP-2 and the bisphosphonate zoledronic acid in a mouse model of NF1-deficient fracture repair.

Fractures were generated in the distal tibiae of neurofibromatosis type 1-deficient (Nf1+/−) mice and control mice. Fractures were open and featured periosteal stripping. All mice received 10 μg rhBMP-2 delivered in a carboxymethylcellulose carrier around the fracture as an anabolic stimulus. Bisphosphonate-treated mice also received five doses of 0.02 mg/kg zoledronic acid given by intraperitoneal injection.

When only rhBMP but no zoledronic acid was used to promote repair, 75% of fractures in Nf1+/− mice remained ununited at three weeks compared with 7% of controls (p < 0.001). Systemic post-operative administration of zoledronic acid halved the rate of ununited fractures to 37.5% (p < 0.07).

These data support the concept that preventing bone loss in combination with anabolic stimulation may improve the outcome following surgical treatment for children with congenital pseudarthoris of the tibia and NF1.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 8 | Pages 1079 - 1083
1 Aug 2011
Choi KJ Lee HS Yoon YS Park SS Kim JS Jeong JJ Choi YR

We reviewed the outcome of distal chevron metatarsal osteotomy without tendon transfer in 19 consecutive patients (19 feet) with a hallux varus deformity following surgery for hallux valgus. All patients underwent distal chevron metatarsal osteotomy with medial displacement and a medial closing wedge osteotomy along with a medial capsular release.

The mean hallux valgus angle improved from −11.6° pre-operatively to 4.7° postoperatively, the mean first-second intermetatarsal angle improved from −0.3° to 3.3° and the distal metatarsal articular angle from 9.5° to 2.3° and the first metatarsophalangeal joints became congruent post-operatively in all 19 feet. The mean relative length ratio of the metatarsus decreased from 1.01 to 0.99 and the mean American Orthopaedic Foot and Ankle Society score improved from 77 to 95 points.

In two patients the hallux varus recurred. One was symptom-free but the other remained symptomatic after a repeat distal chevron osteotomy. There were no other complications.

We consider that distal chevron metatarsal osteotomy with a medial wedge osteotomy and medial capsular release is a useful procedure for the correction of hallux varus after surgery for hallux valgus.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 7 | Pages 955 - 960
1 Jul 2011
Tobler WD Ferrara LA

The presacral retroperitoneal approach for axial lumbar interbody fusion (presacral ALIF) is not widely reported, particularly with regard to the mid-term outcome. This prospective study describes the clinical outcomes, complications and rates of fusion at a follow-up of two years for 26 patients who underwent this minimally invasive technique along with further stabilisation using pedicle screws. The fusion was single-level at the L5-S1 spinal segment in 17 patients and two-level at L4–5 and L5-S1 in the other nine. The visual analogue scale for pain and Oswestry Disability Index scores were recorded pre-operatively and during the 24-month study period. The evaluation of fusion was by thin-cut CT scans at six and 12 months, and flexion-extension plain radiographs at six, 12 and 24 months. Significant reductions in pain and disability occurred as early as three weeks postoperatively and were maintained. Fusion was achieved in 22 of 24 patients (92%) at 12 months and in 23 patients (96%) at 24 months. One patient (4%) with a pseudarthrosis underwent successful revision by augmentation of the posterolateral fusion mass through a standard open midline approach.

There were no severe adverse events associated with presacral ALIF, which in this series demonstrated clinical outcomes and fusion rates comparable with those of reports of other methods of interbody fusion.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 6 | Pages 746 - 750
1 Jun 2011
Zampelis V Ornstein E Franzén H Atroshi I

Previously, radiostereometric analysis following hip revision performed using impacted morsellised allograft bone and a cemented Exeter stem has shown continuous subsidence of the stem for up to five years. It is not known whether the subsidence continues thereafter. In our study, 17 of 25 consecutive osteo-arthritic patients with aseptically loose stems who underwent first-time revision using impacted morsellised allograft bone and a cemented Exeter stem were followed by yearly radiostereometric examinations for nine years. The mean subsidence at six weeks was 1.1 mm (0.1 to 2.3), from six weeks to one year 1.3 mm (0 to 2.6), from one to five years 0.7 mm (0 to 2.0), and from five to nine years 0.7 mm (0.1 to 3.1). That from six weeks to nine years was 2.7 mm (0 to 6.4) (95% confidence interval 2.0 to 3.5). The Charnley pain score significantly improved after revision, and was maintained at nine years, but walking ability deteriorated slightly as follow-up extended. Of the eight patients who were not followed for nine years, two had early subsidence exceeding 11 mm.

Our findings show that in osteo-arthritic patients who undergo revision for aseptic loosening of the stem using impacted morsellised allograft bone and a cemented Exeter stem, migration of the stem continues over nine years at a slower rate after the first year, but without clinical deterioration or radiological loosening.


The Journal of Bone & Joint Surgery British Volume
Vol. 94-B, Issue 5 | Pages 656 - 659
1 May 2012
Hwang B Yoon J Nam C Jung K Lee S Han C Moon S

We retrospectively reviewed 30 two-stage revision procedures in 28 patients performed for fungal peri-prosthetic joint infection (PJI) after a primary total knee replacement. Patients were followed for at least two years or until the infection recurred. The mean follow-up for patients who remained free of infection was 4.3 years (2.3 to 6.1). Overall, 17 patients were assessed as American Society of Anesthesiologists grade 3 or 4. The surgical protocol included removal of the infected implant, vigorous debridement and insertion of an articulating cement spacer. This was followed by at least six weeks of antimicrobial treatment and delayed reimplantation in all patients. The mean interval between removal of the prosthesis and reimplantation was 9.5 weeks (6 to 24). After reimplantation, patients took antifungal agents orally for a maximum of six months. Two knees became reinfected at one and two months post-operatively, respectively: one of these subsequently required arthrodesis because of uncontrolled infection.

Fungal PJIs can be treated successfully by removal of all infected material, appropriate antimicrobial treatment and delayed reimplantation.


The Journal of Bone & Joint Surgery British Volume
Vol. 92-B, Issue 3 | Pages 380 - 386
1 Mar 2010
Niki H Hirano T Okada H Beppu M

Proximal osteotomies for forefoot deformity in patients with rheumatoid arthritis have hitherto not been described. We evaluated combination joint-preserving surgery involving three different proximal osteotomies for such deformities. A total of 30 patients (39 feet) with a mean age of 55.6 years (45 to 67) underwent combined first tarsometatarsal fusion and distal realignment, shortening oblique osteotomies of the bases of the second to fourth metatarsals and a fifth-ray osteotomy.

The mean follow-up was 36 months (24 to 68). The mean foot function index scores for pain, disability and activity subscales were 18, 23, and 16 respectively. The mean Japanese Society for Surgery of the Foot score improved significantly from 52.2 (41 to 68) to 89.6 (78 to 97). Post-operatively, 14 patients had forefoot stiffness, but had no disability. Most patients reported highly satisfactory walking ability. Residual deformity and callosities were absent. The mean hallux valgus and intermetatarsal angles decreased from 47.0° (20° to 67°) to 9.0° (2° to 23°) and from 14.1° (9° to 20°) to 4.6° (1° to 10°), respectively. Four patients had further surgery including removal of hardware in three and a fifth-ray osteotomy in one.

With good peri-operative medical management of rheumatoid arthritis, surgical repositioning of the metatarsophalangeal joint by metatarsal shortening and consequent relaxing of surrounding soft tissues can be successful. In early to intermediate stages of the disease, it can be performed in preference to joint-sacrificing procedures.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 6 | Pages 713 - 719
1 Jun 2011
Duckworth AD Ring D McQueen MM

A suspected fracture of the scaphoid remains difficult to manage despite advances in knowledge and imaging methods. Immobilisation and restriction of activities in a young and active patient must be balanced against the risks of nonunion associated with an undiagnosed and undertreated fracture of the scaphoid.

The assessment of diagnostic tests for a suspected fracture of the scaphoid must take into account two important factors. First, the prevalence of true fractures among suspected fractures is low, which greatly reduces the probability that a positive test will correspond with a true fracture, as false positives are nearly as common as true positives. This situation is accounted for by Bayesian statistics. Secondly, there is no agreed reference standard for a true fracture, which necessitates the need for an alternative method of calculating diagnostic performance characteristics, based upon a statistical method which identifies clinical factors tending to associate (latent classes) in patients with a high probability of fracture.

The most successful diagnostic test to date is MRI, but in low-prevalence situations the positive predictive value of MRI is only 88%, and new data have documented the potential for false positive scans. The best strategy for improving the diagnosis of true fractures among suspected fractures of the scaphoid may well be to develop a clinical prediction rule incorporating a set of demographic and clinical factors which together increase the pre-test probability of a fracture of the scaphoid, in addition to developing increasingly sophisticated radiological tests.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 4 | Pages 479 - 483
1 Apr 2011
Chang C Lai K Yang C Lan S

Between April 2004 and July 2007, we performed 241 primary total knee replacements in 204 patients using the e.motion posterior cruciate-retaining, multidirectional mobile-bearing prosthesis. Of these, 100 were carried out using an image-free navigation system, and the remaining 141 with the conventional technique. We conducted a retrospective study from the prospectively collected data of these patients to assess the early results of this new mobile-bearing design.

At a mean follow-up of 49 months (32 to 71), 18 knees (7.5%) had mechanical complications of which 13 required revision. Three of these had a peri-prosthetic fracture, and were removed from the study. The indication for revision in the remaining ten was loosening of the femoral component in two, tibiofemoral dislocation in three, disassociation of the polyethylene liner in four, and a broken polyethyene liner in one. There were eight further mechanically unstable knees which presented with recurrent disassociation of the polyethylene liner. There was no significant difference in the incidence of mechanical instability between the navigation-assisted procedures (8 of 99, 8.1%) and the conventionally implanted knees (10 of 139, 7.2%).

In our view, the relatively high rate of mechanical complications and revision within 30 months precludes the further use of new design of knee replacement.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 4 | Pages 542 - 547
1 Apr 2011
Bonnard C Fournier J Babusiaux D Planchenault M Bergerault F de Courtivron B

This study evaluated the results of a physeal-sparing technique of intra-articular anterior cruciate ligament (ACL) reconstruction in skeletally immature patients, with particular reference to growth disturbance. Between 1992 and 2007, 57 children with a mean age of 12.2 years (6.8 to 14.5) underwent ACL reconstruction using the same technique. At a mean of 5.5 years (2 to 14) after surgery, 56 patients underwent clinical and radiological evaluation. At that time, 49 patients (87.5%) had reached bony maturity and 53 (95%) achieved A or B according to the IKDC 2000 classification. Four patients had stopped participation in sports because of knee symptoms, and three patients (5.4%) had a subsequent recurrent ACL injury. There was no clinical or radiological evidence of growth disturbance after a mean growth in stature of 20.0 cm (3 to 38).

This study demonstrates that ACL reconstruction sparing the physes in children is a safe technique protecting against meniscal tears and giving better results than reconstruction in adults, without causing significant growth disturbance.


The Journal of Bone & Joint Surgery British Volume
Vol. 93-B, Issue 4 | Pages 470 - 475
1 Apr 2011
Kendrick BJL Simpson DJ Kaptein BL Valstar ER Gill HS Murray DW Price AJ

The Oxford unicompartmental knee replacement (UKR) was designed to minimise wear utilising a fully-congruent, mobile, polyethylene bearing. Wear of polyethylene is a significant cause of revision surgery in UKR in the first decade, and the incidence increases in the second decade. Our study used model-based radiostereometric analysis to measure the combined wear of the upper and lower bearing surfaces in 13 medial-compartment Oxford UKRs at a mean of 20.9 years (17.2 to 25.9) post-operatively.

The mean linear penetration of the polyethylene bearing was 1.04 mm (0.307 to 2.15), with a mean annual wear rate of 0.045 mm/year (0.016 to 0.099). The annual wear rate of the phase-2 bearings (mean 0.022 mm/year) was significantly less (p = 0.01) than that of phase-1 bearings (mean 0.07 mm/year).

The linear wear rate of the Oxford UKR remains very low into the third decade. We believe that phase-2 bearings had lower wear rates than phase-1 implants because of the improved bearing design and surgical technique which decreased the incidence of impingement. We conclude that the design of the Oxford UKR gives low rates of wear in the long term.


The Journal of Bone & Joint Surgery British Volume
Vol. 92-B, Issue 2 | Pages 209 - 216
1 Feb 2010
Pollard TCB Villar RN Norton MR Fern ED Williams MR Murray DW Carr AJ

Femoroacetabular impingement causes pain in the hip in young adults and may predispose to the development of osteoarthritis. Genetic factors are important in the aetiology of osteoarthritis of the hip and may have a role in that of femoroacetabular impingement. We compared 96 siblings of 64 patients treated for primary impingement with a spouse control group of 77 individuals. All the subjects were screened clinically and radiologically using a standardised protocol for the presence of cam and pincer deformities and osteoarthritis.

The siblings of those patients with a cam deformity had a relative risk of 2.8 of having the same deformity (66 of 160 siblings hips versus 23 of 154 control hips, p < 0.00001). The siblings of those patients with a pincer deformity had a relative risk of 2.0 of having the same deformity (43 of 116 sibling hips versus 29 of 154 control hips, p = 0.001). Bilateral deformity occurred more often in the siblings (42 of 96 siblings versus 13 of 77 control subjects, relative risk 2.6, p = 0.0002). The prevalence of clinical features in those hips with abnormal morphology was also greater in the sibling group compared with the control group (41 of 109 sibling hips versus 7 of 46 control hips, relative risk 2.5, p = 0.007). In 11 sibling hips there was grade-2 osteoarthritis according to Kellgren and Lawrence versus none in the control group (p = 0.002).

Genetic influences are important in the aetiology of primary femoroacetabular impingement. This risk appears to be manifested through not only abnormal joint morphology, but also through other factors which may modulate progression of the disease.