Joint Morphogenesis and Its Roles in Joint Biomechanics and Health

Background It remains unclear if femoral retroversion is a contraindication for hip arthroscopy in patients with femoroacetabular impingement (FAI). Purpose To compare the area and location of hip impingement at maximal flexion and during the FADIR test (flexion, adduction, internal rotation) in FAI hips with femoral retroversion, hips with decreased combined version, and asymptomatic controls. Study Design Cross-sectional study; Level of evidence, 3. Methods Twenty-four symptomatic patients (37 hips) with anterior FAI were evaluated. All patients had femoral version (FV) <5° according to the Murphy method. Two subgroups were analyzed: 13 hips with absolute femoral retroversion (FV <0°) and 29 hips with decreased combined version (McKibbin index <20°). All patients were symptomatic and had anterior groin pain and a positive anterior impingement test ; all had undergone pelvic computed tomography (CT) scans to measure FV. The asymptomatic control group consisted of 26 hips. Dynamic impingement simulation of maximal flexion and FADIR test at 90° of flexion was performed with patient-specific CT-based 3-dimensional models. Extra- or intra-articular hip impingement area and location were compared between the subgroups and with control hips using nonparametric tests. Results Impingement area was significantly larger for hips with decreased combined version (<20°) versus combined version (≥20°) (mean ± SD; 171 ± 140 vs 78 ± 55 mm ² ; P = .012) and was significantly larger for hips with FV <0° (absolute femoral retroversion) vs FV >0° ( P = .025). Hips with absolute femoral retroversion had a significantly higher frequency of extra-articular subspine impingement versus controls (92% vs 0%; P < .001), compared to 84% of patients with decreased combined version. Intra-articular femoral impingement location was most often (95%) anterosuperior and anterior (2-3 o’clock). Anteroinferior femoral impingement location was significantly different at maximal flexion (anteroinferior [4-5 o’clock]) versus the FADIR test (anterosuperior and anterior [2-3 o’clock]) ( P < .001). Conclusion Patients with absolute femoral retroversion (FV <0°) had a larger hip impingement area, and most exhibited extra-articular subspine impingement. Preoperative FV assessment with advanced imaging (CT/magnetic resonance imaging) could help to identify these patients (without 3-dimensional modeling). Femoral impingement was located anteroinferiorly at maximal flexion and anterosuperiorly and anteriorly during the FADIR test.

Background: Severe slipped capital femoral epiphysis (SCFE) leads to femoroacetabular impingement and restricted hip motion. We investigated the improvement of impingement-free flexion and internal rotation (IR) in 90 degrees of flexion following a simulated osteochondroplasty, a derotation osteotomy, and a combined flexion-derotation osteotomy in severe SCFE patients using 3D-CT-based collision detection software. Methods: Preoperative pelvic CT of 18 untreated patients (21 hips) with severe SCFE (slip-angle>60 degrees) was used to generate patient-specific 3D models. The contralateral hips of the 15 patients with unilateral SCFE served as the control group. There were 14 male hips (mean age 13±2 y). No treatment was performed before CT. Specific collision detection software was used for the calculation of impingement-free flexion and IR in 90 degrees of flexion and simulation of osteochondroplasty, derotation osteotomy, and combined flexion-derotation osteotomy. Results: Osteochondroplasty alone improved impingement-free motion but compared with the uninvolved contralateral control group, severe SCFE hips had persistently significantly decreased motion (mean flexion 59±32 degrees vs. 122±9 degrees, P<0.001; mean IR in 90 degrees of flexion -5±14 degrees vs. 36±11 degrees, P<0.001). Similarly, the impingement-free motion was improved after derotation osteotomy, and impingement-free flexion after a 30 degrees derotation was equivalent to the control group (113± 42 degrees vs. 122±9 degrees, P=0.052). However, even after the 30 degrees derotation, the impingement-free IR in 90 degrees of flexion persisted lower (13±15 degrees vs. 36±11 degrees, P<0.001). Following the simulation of flexion-derotation osteotomy, mean impingement-free flexion and IR in 90 degrees of flexion increased for combined correction of 20 degrees (20 degrees flexion and 20 degrees derotation) and 30 degrees (30 degrees flexion and 30 degrees derotation). Although mean flexion was equivalent to the control group for both (20 degrees and 30 degrees) combined correction, the mean IR in 90 degrees of flexion persisted decreased, even after the 30 degrees combined flexion-derotation (22±22 degrees vs. 36 degrees±11, P=0.009). Conclusions: Simulation of derotation-osteotomy (30 degrees correction) and flexion-derotation-osteotomy (20 degrees correction) normalized hip flexion for severe SCFE patients, but IR in 90 degrees of flexion persisted slightly lower despite significant improvement. Not all SCFE patients had improved hip motion with the performed simulations; therefore, some patients may need a higher degree of correction or combined treatment with osteotomy and cam-resection, although not directly investigated in this study. Patient-specific 3D-models could help individual preoperative planning for severe SCFE patients to normalize the hip motion. Level of evidence: III, case-control study.

Background: Several anatomic risk factors have been identified in the pathogenesis of patellofemoral instability. The literature is sparce regarding how these anatomic risk factors change during skeletal growth and development. Hypothesis: The anatomic risk factors associated with patellar instability change significantly during skeletal growth and maturation with different patterns in male versus female patients. Study design: Cross-sectional study; Level of evidence, 3. Methods: Magnetic resonance imaging data from 240 unique, asymptomatic knees (7-18 years of age; 50% female) were used to measure patellar height (Caton-Deschamps index), lateral patellar tilt angle, trochlear height, trochlear groove depth, trochlear sulcus angle, and tibial tubercle-trochlear groove (TT-TG) distance. Linear regression was used to test the associations between age and anatomic findings. Two-way analysis of variance with Holm-Šídák post hoc test was used to compare anatomic characteristics between sexes in 3 age groups: prepubertal school-aged children (7-10 years old), early adolescents (11-14 years old), and late adolescents (15-18 years old). Results: Patellar height (female sex), lateral patellar tilt angle (male sex), and trochlear sulcus angle (both sexes) decreased with age (P < .001). Trochlear height, depth, and TT-TG distance increased with age in both male and female participants (P < .02). Male participants had a larger sulcus angle (by 5.3°± 1.6° at age 11-14 years) and greater trochlear height (by >5 mm across medial, central, and lateral regions at age 15-18 years) than age-matched female participants (P < .01). We found no other sex-related differences in quantified anatomic features (P > .1). Conclusion: The findings partially support our hypothesis indicating significant age-related changes in all quantified features, which were not different between male and female participants except for trochlear sulcus angle in early adolescence and trochlear height in late adolescence. In general, the majority of anatomic risk factors for patellar instability change with maturity in a direction that assists in reducing the risk of patellar instability and/or dislocation. The only outlier is the TT-TG distance, which increased by age, and in our oldest cohort of patients, the mean fell below the normal adult range. The current observations highlight the importance of age in the interpretation of risk for injury as well as the need for further studies to identify intrinsic and extrinsic factors that may result in abnormal development of these anatomic features during skeletal growth and maturation.

Introduction: Slipped capital femoral epiphysis (SCFE) is the most common hip disorder in adolescent patients that can result in complex 3 dimensional (3D)-deformity and hip preservation surgery (eg, in situ pinning or proximal femoral osteotomy) is often performed. But there is little information about location of impingement.Purpose/Questions: The purpose of this study was to evaluate (1) impingement-free hip flexion and internal rotation (IR), (2) frequency of impingement in early flexion (30 to 60 degrees), and (3) location of acetabular and femoral impingement in IR in 90 degrees of flexion (IRF-90 degrees) and in maximal flexion for patients with untreated severe SCFE using preoperative 3D-computed tomography (CT) for impingement simulation. Methods: A retrospective study involving 3D-CT scans of 18 patients (21 hips) with untreated severe SCFE (slip angle>60 degrees) was performed. Preoperative CT scans were used for bone segmentation of preoperative patient-specific 3D models. Three patients (15%) had bilateral SCFE. Mean age was 13±2 (10 to 16) years and 67% were male patients (86% unstable slip, 81% chronic slip). The contralateral hips of 15 patients with unilateral SCFE were evaluated (control group). Validated software was used for 3D impingement simulation (equidistant method). Results: (1) Impingement-free flexion (46±32 degrees) and IRF-90 degrees (-17±18 degrees) were significantly (P<0.001) decreased in untreated severe SCFE patients compared with contralateral side (122±9 and 36±11 degrees).(2) Frequency of impingement was significantly (P<0.001) higher in 30 and 60 degrees flexion (48% and 71%) of patients with severe SCFE compared with control group (0%).(3) Acetabular impingement conflict was located anterior-superior (SCFE patients), mostly 12 o'clock (50%) in IRF-90 degrees (70% on 2 o'clock for maximal flexion). Femoral impingement was located on anterior-superior to anterior-inferior femoral metaphysis (between 2 and 6 o'clock, 40% on 3 o'clock and 40% on 5 o'clock) in IRF-90 degrees and on anterior metaphysis (40% on 3 o'clock) in maximal flexion and frequency was significantly (P<0.001) different compared with control group. Conclusion: Severe SCFE patients have limited hip flexion and IR due to early hip impingement using patient-specific preoperative 3D models. Because of the large variety of hip motion, individual evaluation is recommended to plan the osseous correction for severe SCFE patients. Level of evidence: Level III.

Aims To evaluate how abnormal proximal femoral anatomy affects different femoral version measurements in young patients with hip pain. Methods First, femoral version was measured in 50 hips of symptomatic consecutively selected patients with hip pain (mean age 20 years (SD 6), 60% (n = 25) females) on preoperative CT scans using different measurement methods: Lee et al, Reikerås et al, Tomczak et al, and Murphy et al. Neck-shaft angle (NSA) and α angle were measured on coronal and radial CT images. Second, CT scans from three patients with femoral retroversion, normal femoral version, and anteversion were used to create 3D femur models, which were manipulated to generate models with different NSAs and different cam lesions, resulting in eight models per patient. Femoral version measurements were repeated on manipulated femora. Results Comparing the different measurement methods for femoral version resulted in a maximum mean difference of 18° (95% CI 16 to 20) between the most proximal (Lee et al) and most distal (Murphy et al) methods. Higher differences in proximal and distal femoral version measurement techniques were seen in femora with greater femoral version ( r > 0.46; p < 0.001) and greater NSA ( r > 0.37; p = 0.008) between all measurement methods. In the parametric 3D manipulation analysis, differences in femoral version increased 11° and 9° in patients with high and normal femoral version, respectively, with increasing NSA (110° to 150°). Conclusion Measurement of femoral version angles differ depending on the method used to almost 20°, which is in the range of the aimed surgical correction in derotational femoral osteotomy and thus can be considered clinically relevant. Differences between proximal and distal measurement methods further increase by increasing femoral version and NSA. Measurement methods that take the entire proximal femur into account by using distal landmarks may produce more sensitive measurements of these differences. Cite this article: Bone Jt Open 2022;3(10):759–766.

Background Patellofemoral disorders account for approximately 25% of patients seen in sports medicine clinics. A variety of anatomic risk factors have been identified in the pathogenesis of patellofemoral instability. While studies have analyzed these factors in adults, or compared them between healthy controls and patients with patellar injuries, little is known about how these anatomic markers change during skeletal growth and development. Hypothesis/Purpose (A) The anatomic risk factors associated with patellar instability and dislocation change significantly during skeletal maturation. (B) These age-related changes during maturation will differ between male and female patients. Methods After institutional review board approval, magnetic resonance imaging data from 239 unique knees (patient age 7-18; 55% female), without previous or current injury, were randomly selected and used to measure patellar height, lateral patellar tilt angle, trochlear width, trochlear depth, trochlear sulcus angle, and tibial tubercle trochlear groove distance. Linear regression was used to test the associations between age and anatomic measurement indices. Subsequently, patients were divided into four age groups: pre-pubertal school-aged children (7-10 years old), early adolescents (11-14 years old), and late adolescents (15-18 years old). Additionally, two-way analysis of variance with the Holm-Sidak post hoc test was used to compare anatomic morphologies between male and female patients in each age group. Results Patellar height (Caton-Deschamps index), lateral patellar tilt angle and trochlear sulcus angle all decreased significantly with age (P<0.001). Trochlear width, depth, and tibial tubercule trochlear groove distance all increased significantly with age (P<0.001). Except for trochlear width in late adolescence (P<0.001) where males had wider trochlea (medial and lateral) compared to matched females, the age-related anatomic changes were similar between males and females (P>0.1). Conclusion The findings partially support our hypothesis, as we observed significant age-related changes in all quantified anatomical indices, which was not different (except trochlear width in late adolescence) between males and females. The lack of significant differences in key morphological features of the patellofemoral joint that are linked to patellar dislocation between females and males is consistent with a similar prevalence of this injury between the two. However, the findings suggest that there are significant differences in the trochlear width between females and males at later stages of growth and maturation. The current observations suggest that these anatomic risk factors undergo significant changes during skeletal growth, providing us with a window of opportunity to use prophylactic interventions to prevent or minimize the development of high-risk morphology. [Figure: see text][Figure: see text]

Given GDF5 involvement in hip development, and osteoarthritis (OA) and developmental hip dysplasia (DDH) risk, here we sought to assess the role(s) of GDF5 and its regulatory sequence on the development of hip morphology linked to injury risk. The brachypodism (bp) mouse, which harbors a Gdf5 inactivating mutation, was used to survey how Gdf5 loss of function impacts the development of hip morphology. Two transgenic Gdf5 reporter BAC lines were used to assess the spatiotemporal expression of Gdf5 regulatory sequences. Each BAC line was also used to assess the functional roles of upstream and downstream sequence on hip morphology. bp/bp mice had shorter femora with smaller femoral heads and necks as well as larger alpha angles, smaller anterior offsets, and smaller acetabula, compared to bp/+ mice (p<0.04). Regulatory sequences downstream of Gdf5 drove strong prenatal (E17) expression and low postnatal (6 months) expression across regions of femoral head and acetabulum. Conversely, upstream regulatory sequences drove very low expression at E17 and no detectable expression at 6 months. Importantly, downstream, but not upstream Gdf5 regulatory sequences fully restored all the key morphologic features disrupted in bp/bp mice. Hip morphology is profoundly affected by Gdf5 absence, and downstream regulatory sequences mediate its effects by controlling Gdf5 expression during development. This downstream region contains numerous enhancers harboring risk variants related to hip OA, DDH, and dislocation. We posit that subtle alterations to morphology driven by changes in downstream regulatory sequence underlie this locus’ role in hip injury risk.

The epiphyseal tubercle plays an important role in epiphyseal stabilization. While the majority of studies have focused on tubercle morphology, there is a paucity of information on the morphological features of the metaphyseal fossa, where tubercle sits on the metaphysis. The goal of this study was to determine the developmental changes in the capital femoral metaphyseal fossa. Computed tomography of the pelvis from 80 children and adolescents 8‐15 years old were used to create 3‐dimensional models of the proximal femur. Depth, width, length and surface area of the metaphyseal fossa were measured and the impact of age and sex on fossa morphology was assessed using the linear regression and two‐way ANOVA respectively. The metaphyseal fossa was located in the postero‐superior quadrant of the metaphysis without any variations in the location with increasing age (P>0.1). However, with increasing age there was a reduction in all metaphyseal fossa measurements including the depth, length, width, and surface area (P<0.01). No significant differences were noted for the metaphyseal fossa measurements between males and females (P>0.1). The metaphyseal fossa reduces in size from 8 to 15 years of age in a similar fashion in males and females. As the metaphyseal fossa adjacent to the tubercle matches the area where a focal radiolucency has been observed in early slipped capital femoral epiphysis (SCFE), further studies should clarify the mechanisms by which the interlocking interaction of the epiphyseal tubercle and its fossa contributes to or is affected by SCFE. This article is protected by copyright. All rights reserved.

During human evolution, the knee adapted to the biomechanical demands of bipedalism by altering chondrocyte developmental programs. This adaptive process was likely not without deleterious consequences to health. Today, osteoarthritis occurs in 250 million people, with risk variants enriched in non-coding sequences near chondrocyte genes, loci that likely became optimized during knee evolution. We explore this relationship by epigenetically profiling joint chondrocytes, revealing ancient selection and recent constraint and drift on knee regulatory elements, which also overlap osteoarthritis variants that contribute to disease heritability by tending to modify constrained functional sequence. We propose a model whereby genetic violations to regulatory constraint, tolerated during knee development, lead to adult pathology. In support, we discover a causal enhancer variant (rs6060369) present in billions of people at a risk locus (GDF5-UQCC1), showing how it impacts mouse knee-shape and osteoarthritis. Overall, our methods link an evolutionarily novel aspect of human anatomy to its pathogenesis.

The quality of a repaired anterior cruciate ligament (ACL) or reconstructed graft is typically quantified by evaluating knee, lower extremity or subject performance. However, magnetic resonance (MR) imaging of the healing ACL or graft provides a more direct measure of the tissue quality (i.e., signal intensity) and quantity (i.e., cross-sectional area). Here we used a quantitative MR imaging approach to evaluate longitudinal changes in graft size and signal intensity over the first 2 years after ACL reconstruction (ACLR). We also studied the structural changes in ACLs treated with a novel surgical repair procedure, Bridge-Enhanced ACL Repair (BEAR). We hypothesized that there would be differences in the cross-sectional area or signal intensity of the repaired ACL or reconstructed graft within 2 years after surgery, and that these structural properties correlate with knee anatomy.

Background: The inner surface of the capital femoral epiphysis is important for growth plate stability. However, abnormalities of epiphyseal morphology associated with the pathogenesis of slipped capital femoral epiphysis (SCFE) remain poorly understood. This study compares the 3-dimensional anatomy of the epiphyseal tubercle and peripheral cupping in hips with SCFE and normal hips. Methods: We created 3-dimensional models of the capital femoral epiphysis with use of computed tomography (CT) imaging from 51 patients with SCFE and 80 subjects without hip symptoms who underwent CT because of abdominal pain. The height, width, and length of the epiphyseal tubercle and the peripheral cupping were measured and normalized by the epiphyseal diameter and presented as a percentage. We used analysis of variance for the comparison of the measurements between SCFE and control hips after adjusting for age and sex. Results: Compared with normal hips, hips with mild SCFE had smaller mean epiphyseal tubercle height (0.9% ± 0.9% compared with 4.4% ± 0.4%; p = 0.006) and length (32.3% ± 1.8% compared with 43.7% ± 0.8%; p < 0.001). The mean epiphyseal tubercle height was also smaller in hips with moderate (0.6% ± 0.9%; p = 0.004) and severe SCFE (0.3% ± 0.8%; p < 0.001) compared with normal hips. No differences were observed for measurements of epiphyseal tubercle height and length between SCFE subgroups. The mean peripheral cupping was larger in hips with mild (16.3% ± 1.0%; p < 0.001), moderate (16.4% ± 1.1%; p < 0.001), and severe SCFE (18.9% ± 0.9%; p < 0.001) overall and when assessed individually in all regions compared with normal hips (10.6% ± 0.5%). Conclusions: Hips with SCFE have a smaller epiphyseal tubercle and larger peripheral cupping compared with healthy hips. A smaller epiphyseal tubercle may be a predisposing morphologic factor or a consequence of the increased shearing stress across the physis secondary to the slip. Increased peripheral growth may be an adaptive response to instability as other stabilizers (i.e., epiphyseal tubercle and anterior periosteum) become compromised with slip progression. Future studies are necessary to determine the biomechanical basis of our morphologic findings.

Background: Primary repair of the anterior cruciate ligament (ACL) augmented with a tissue engineered scaffold to facilitate ligament healing is a technique under development for patients with ACL injuries. The size (the amount of tissue) and signal intensity (the quality of tissue) of the healing ligament as visualized on magnetic resonance imaging (MRI) have been shown to be related to its strength in large animal models. Hypothesis: Both modifiable and nonmodifiable risk factors could influence the size and signal intensity of the repaired ligament in patients at 6 months after surgery. Study design: Case series; Level of evidence, 4. Methods: 62 patients (mean age, 19.4 years; range, 14-35 years) underwent MRI of the knee 6 months after ACL repair augmented with an extracellular matrix scaffold. The signal intensity (normalized to cortical bone) and average cross-sectional area of the healing ligament were measured from the MRI stack obtained by use of a gradient echo sequence. Associations between these 2 measures and patient characteristics, which included demographic, clinical, and anatomic features, were determined by use of multivariable regression analysis. Results: A larger cross-sectional area of the repaired ligament at 6 months was associated with male sex, older age, and the performance of a larger notchplasty ( P < .05 for all associations). A lower signal intensity at 6 months, indicating greater similarity to normal ligament, was associated with a smaller tibial slope and greater side-to-side difference in quadriceps strength 3 months after surgery. Other factors, including preoperative body mass index, mechanism of injury, tibial stump length, and Marx activity score, were not significantly associated with either MRI parameter at 6 months. Conclusion: Modifiable factors, including surgical notchplasty and slower recovery of quadriceps strength at 3 months, were associated with a larger cross-sectional area and improved signal intensity of the healing ACL after bridge-enhanced ACL repair in this preliminary study. Further studies to determine the optimal size of the notchplasty and the most effective postoperative rehabilitation strategy after ACL repair augmented by a scaffold are justified. Registration: NCT02664545 (ClinicalTrials.gov identifier).

Background: The quality of a repaired anterior cruciate ligament (ACL) or reconstructed graft is typically quantified in clinical studies by evaluating knee, lower extremity, or patient performance. However, magnetic resonance imaging of the healing ACL or graft may provide a more direct measure of tissue quality (ie, signal intensity) and quantity (ie, cross-sectional area). Hypotheses: (1) Average cross-sectional area or signal intensity of a healing ACL after bridge-enhanced ACL repair (BEAR) or a hamstring autograft (ACL reconstruction) will change postoperatively from 3 to 24 months. (2) The average cross-sectional area and signal intensity of the healing ligament or graft will correlate with anatomic features of the knee associated with ACL injury. Study design: Cohort study; Level of evidence, 2. Methods: Patients with a complete midsubstance ACL tear who were treated with either BEAR (n = 10) or ACL reconstruction (n = 10) underwent magnetic resonance imaging at 3, 6, 12, and 24 months after surgery. Images were analyzed to determine the average cross-sectional area and signal intensity of the ACL or graft at each time point. ACL orientation, stump length, and bony anatomy were also assessed. Results: Mean cross-sectional area of the grafts was 48% to 98% larger than the contralateral intact ACLs at all time points ( P < .01). The BEAR ACLs were 23% to 28% greater in cross-sectional area than the contralateral intact ACLs at 3 and 6 months ( P < .02) but similar at 12 and 24 months. The BEAR ACLs were similar in sagittal orientation to the contralateral ACLs, while the grafts were 6.5° more vertical ( P = .005). For the BEAR ACLs, a bigger notch correlated with a bigger cross-sectional area, while a shorter ACL femoral stump, steeper lateral tibial slope, and shallower medial tibial depth were associated with higher signal intensity ( R2 > .40, P < .05). Performance of notchplasty resulted in an increased ACL cross-sectional area after the BEAR procedure ( P = .007). No anatomic features were correlated with ACL graft size or signal intensity. Conclusion: Hamstring autografts were larger in cross-sectional area and more vertically oriented than the native ACLs at 24 months after surgery. BEAR ACLs had a cross-sectional area, signal intensity, and sagittal orientation similar to the contralateral ACLs at 24 months. The early signal intensity and cross-sectional area of the repaired ACL may be affected by specific anatomic features, including lateral tibial slope and notch width-observations that deserve further study in a larger cohort of patients. Registration: NCT02292004 (ClinicalTrials.gov identifier).

Epiphyseal tubercle and peripheral cupping can influence the development of slipped capital femoral epiphysis (SCFE) and Cam morphology. During normal skeletal growth, epiphyseal tubercle shrinks while the peripheral cupping grows. We hypothesized that epiphyseal tubercle act as the primary stabilizer of the head‐neck junction at early stages and this role is gradually transferred to epiphyseal cupping as the tubercle shrinks and cupping grows. From a cohort of 80 boys and girls (8–15 years old) with normal hips, CT scans of 5 subjects corresponding to minimum, 25th percentile, median, 75th percentile and maximum relative tubercle and cupping height were used to develop 3D finite element models. In vivo measured hip loads were used to study load sharing between the tubercle and peripheral cupping under combined and uniaxial loads exerted on femoral head during a range of daily activities. Lower epiphyseal tubercle height, larger epiphyseal cupping height and bigger differences in tubercle and cupping heights were strongly associated with increased epiphyseal cupping to epiphyseal tubercle stress ratios (R2 > 0.7). We found lower peripheral cupping stresses relative to the tubercle (cupping to tubercle stress ratio <1) in hips with larger tubercle and smaller cupping. The relative decreases in tubercle size along with increased in peripheral cupping in our models gradually shifted the load distribution to higher stresses in the periphery compared to the epiphyseal tubercle area (cupping to tubercle stress ratio >1). Both tubercle and cupping play a substantial role in sharing the generated stresses across the head‐neck junction under all tested loading conditions. This article is protected by copyright. All rights reserved

The intra-epiphyseal growth of the proximal femur has been focus of studies because of the potential relationship with the development of slipped capital femoral epiphysis and cam deformity in femoroacetabular impingement. We aimed to evaluate the developmental pattern of the epiphyseal tubercle and extension in normal boys and girls from eight to fifteen years, without hip conditions. We performed three-dimensional (3D) analysis of pelvic computed tomographic scans of 80 subjects with suspect of appendicitis, consisting of five boys and five girls for each age, from eight to 15 years old. Images were segmented slice by slice at the level of the growth plate using biplanar orientation. The 3D-segmented epiphyses were used to measure the location and height of the tubercle, the height of the epiphyseal extension, and the epiphyseal diameter. We found that the epiphyseal tubercle was eccentrically located at the posterolateral quadrant of the physeal surface. The absolute height of the epiphyseal tubercle did not vary between ages (R2=0.04; p=0.101). The epiphyseal diameter increased with age (R2=0.74; p<0.001), making the tubercle height proportionally smaller with the epiphyseal growth (9% reduction in tubercle height normalised by the epiphyseal diameter). The normalised epiphyseal extension height significantly increased by 160% from 8 to 15 years of age. Our observation validates the hypothesis of the cupping mechanism provided by the peripheral growth of the epiphyseal extension, while the epiphyseal tubercle relatively decreases in size during the skeletal growth. Further research will be important to determine the role of these structures in the epiphyseal stability.

Background Understanding the development of the capital femoral epiphysis is essential to identify pathologic variations that may lead to cam morphology. Purpose/Hypothesis The purpose of this study was to investigate the development of the capital femoral epiphysis during childhood and adolescence, with specific morphologic analysis of the peripheral growth and the metaphyseal surface of the growth plate. We hypothesized that age- and sex-dependent morphologic variations of the peripheral growth (cupping) and surface anatomy (epiphyseal tubercle) of the epiphysis would be evident with increasing age. Study Design Cross-sectional study; Level of evidence, 3. Methods Pelvic computed tomography scans of 80 children and adolescents (range, 8-15 years; n = 10 per age group; 50% male), imaged because of suspected appendicitis, were used to reformat the proximal femur. All patients had asymptomatic hips with no signs or history of hip disorder. We measured the peripheral cupping of the epiphysis and the epiphyseal tubercle dimensions from 3-dimensional models. All measurements were normalized to the epiphyseal diameter. The effect of age on these parameters was evaluated by use of linear regression analysis. A 2-way analysis of variance (ANOVA) was used to compare these parameters between males and females. Results The mean epiphyseal cupping increased with increasing age (R² = 0.54; P < .001). The mean normalized epiphyseal cupping was consistently higher in the anterior and posterior directions compared with the inferior and superior locations. Male patients aged 10 and 11 years had lower (P = .002) mean epiphyseal cupping compared with female patients of the same age. We observed no difference between male and female participants after 12 years of age (P > .3). The normalized epiphyseal tubercle height (R² = 0.08; P = .009), width (R² = 0.13; P = .001), and length (R² = 0.45; P < .001) decreased with increasing age, with no differences between male and female patients. On average, a 2.6-fold increase was found in epiphyseal cupping from 8 to 15 years of age, whereas normalized tubercle height decreased by 0.4-fold. Conclusion Peripheral cupping of the epiphysis over the metaphysis increases with age, while the relative epiphyseal tubercle dimensions decrease. Females have an earlier onset of rapid increase in the peripheral cupping compared with males; however, no differences in epiphyseal tubercle dimensions were found between male and female patients. These findings may guide future studies investigating the development of cam morphology, which should consider the surface morphologic characteristics of the capital femoral epiphysis, the growth plate, and the differences in morphologic characteristics according to age and sex.

Given GDF5 involvement in hip development, and osteoarthritis (OA) and developmental hip dysplasia (DDH) risk, here we sought to assess the role(s) of GDF5 and its regulatory sequence on the development of hip morphology linked to injury risk. The brachypodism (bp) mouse, which harbors a Gdf5 inactivating mutation, was used to survey how Gdf5 loss of function impacts the development of hip morphology. Two transgenic Gdf5 reporter BAC lines were used to assess the spatiotemporal expression of Gdf5 regulatory sequences. Each BAC line was also used to assess the functional roles of upstream and downstream sequence on hip morphology. bp/bp mice had shorter femora with smaller femoral heads and necks as well as larger alpha angles, smaller anterior offsets, and smaller acetabula, compared to bp/+ mice (p<0.04). Regulatory sequences downstream of Gdf5 drove strong prenatal (E17) expression and low postnatal (6 months) expression across regions of femoral head and acetabulum. Conversely, upstream regulatory sequences drove very low expression at E17 and no detectable expression at 6 months. Importantly, downstream, but not upstream Gdf5 regulatory sequences fully restored all the key morphologic features disrupted in bp/bp mice. Hip morphology is profoundly affected by Gdf5 absence, and downstream regulatory sequences mediate its effects by controlling Gdf5 expression during development. This downstream region contains numerous enhancers harboring risk variants related to hip OA, DDH, and dislocation. We posit that subtle alterations to morphology driven by changes in downstream regulatory sequence underlie this locus’ role in hip injury risk.

Objectives Given the role of growth and differentiation factor 5 (GDF5) in knee development and osteoarthritis risk, we sought to characterise knee defects resulting from Gdf5 loss of function and how its regulatory regions control knee formation and morphology. Methods The brachypodism (bp) mouse line, which harbours an inactivating mutation in Gdf5, was used to survey how Gdf5 loss of function impacts knee morphology, while two transgenic Gdf5 reporter bacterial artificial chromosome mouse lines were used to assess the spatiotemporal activity and function of Gdf5 regulatory sequences in the context of clinically relevant knee anatomical features. Results Knees from homozygous bp mice (bp/bp) exhibit underdeveloped femoral condyles and tibial plateaus, no cruciate ligaments, and poorly developed menisci. Secondary ossification is also delayed in the distal femur and proximal tibia. bp/bp mice have significantly narrower femoral condyles, femoral notches and tibial plateaus, and curvier medial femoral condyles, shallower trochlea, steeper lateral tibial slopes and smaller tibial spines. Regulatory sequences upstream from Gdf5 were weakly active in the prenatal knee, while downstream regulatory sequences were active throughout life. Importantly, downstream but not upstream Gdf5 regulatory sequences fully restored all the key morphological features disrupted in the bp/bp mice. Conclusions Knee morphology is profoundly affected by Gdf5 absence, and downstream regulatory sequences mediate its effects by controlling Gdf5 expression in knee tissues. This downstream region contains numerous enhancers harbouring human variants that span the osteoarthritis association interval. We posit that subtle alterations to morphology driven by changes in downstream regulatory sequence underlie this locus’ role in osteoarthritis risk.

Knee joint is the most common site of injury in children and adolescents and accounts for up to 60% of all sports-related injuries in this population. Ruptures of the anterior cruciate ligament (ACL) are among the most frequent knee injuries in pediatric population with up to 10 times greater prevalence in females than males. These injuries are often immediately disabling and are associated with significant short- and long-term clinical compilations such as increased risk of posttraumatic osteoarthritis (OA), despite our best current treatment methods. Several unique anatomical features of the knee joint, including tibial slope and femoral notch size, have shown to affect joint and ACL loading and risk of injury. Despite the well-established role of these anatomical features on ACL injury risk, it remains unclear how these anatomical features change during skeletal growth and maturation. We are proposing to systematically investigate how age and sex affect multiple prominent anatomical features of the knee joint in children and adolescents. This will be done retrospectively by analyzing the Magnetic Resonance (MR) images of the knees of patients who underwent a knee MRI at Boston Children’s Hospital. The 3D MR image stacks will be used to measure a comprehensive set of anatomical indices of the knee joint based on previously established techniques. The associations between age and each of the quantified anatomical indices will be assessed. The age-dependent changes in knee anatomy will be compared between boys and girls as well as between those who had an ACL injury and those with healthy uninjured knees. Findings will help to better understand how prominent anatomical features of the knee joint, in particular those identified as risk factors for ACL injury, are being developed and/or changed during skeletal growth and maturation. Findings will also improve our knowledge of how sex may affect the age dependent changes in knee anatomy. The outcomes of this work will improve our knowledge on how and when anatomy becomes different between subjects at low risk of ACL injury and “at risk” population. Such improved knowledge can be used to develop novel risk screening models to more effectively identify children at high risk of ACL injury based on their anatomical profile. Individuals with high-risk bony anatomy can be subjected to neuromuscular and biomechanical interventions early on to minimize their risk of sustaining and ACL tear.