Rhizomelia and Impaired Linear Growth in a Girl with Juvenile Paget Disease: The Natural History of the Condition.

In ultra-rare bone diseases, information on growth during childhood is sparse. Juvenile Paget disease (JPD) is an ultra-rare disease, characterized by loss of function of osteoprotegerin (OPG). OPG inhibits osteoclast activation via the receptor activator of nuclear factor-κB (RANK) pathway. In JPD, overactive osteoclasts result in inflammatory-like bone disease due to grossly elevated bone resorption. Knowledge on the natural history of JPD, including final height and growth, is limited. Most affected children receive long-term antiresorptive treatment, mostly with bisphosphonates, to contain bone resorption, which may affect growth. In this study, we report the follow-up of height, growth velocity, and skeletal maturation in a 16-year-old female patient with JPD. The patient was treated with cyclic doses of pamidronate starting at 2.5 years of age and with 2 doses of denosumab at the age of 8 years, when pamidronate was paused. In the following years, a sustainable decline in a height z-score and a stunted pubertal growth spurt; despite appropriate maturation of the epiphyseal plates of the left hand, the proximal right humerus and both femora were observed. Whether this reflects the growth pattern in JPD or might be associated to the antiresorptive treatments is unclear, since there is very limited information available on the effect of bisphosphonates and denosumab on growth and the growth plate in pediatric patients. Studies are needed to understand the natural history of an ultra-rare bone disease and to assess the effects of antiresorptive treatment on the growing skeleton.

Lower-Extremity Segment-Length Prediction Accuracy of the Sanders Multiplier, Paley Multiplier, and White-Menelaus Formula.

BACKGROUND: Several methods are available to estimate leg lengths at maturity to facilitate the determination of timing of epiphysiodesis. We compared the Paley multiplier, Sanders multiplier, and White-Menelaus methods in an epiphysiodesis-aged cohort. We assessed intra- and interrater reliability for Sanders skeletal stages and Greulich and Pyle atlas skeletal age. METHODS: Actual growth was recorded in healthy, unoperated femoral and tibial segments from an epiphysiodesis database. The predicted and actual lengths were compared with use of the Paley multiplier and White-Menelaus methods, Greulich and Pyle skeletal age, and the Sanders multiplier using Sanders stages. Intra- and interrater reliability were assessed in a separate group of 76 skeletal age films. RESULTS: The cohort included 148 femora and 195 tibiae in 197 patients. Femoral length at maturity was slightly underestimated by the Sanders multiplier and staging, was overestimated by the Paley multiplier and skeletal age, and was most accurately predicted with use of the White-Menelaus formula and skeletal age. All methods overestimated tibial length at maturity. The whole-leg prediction accuracy of the Sanders multiplier and White-Menelaus formula were comparable and were more accurate than that of the Paley multiplier. For Sanders skeletal staging, the interrater reliability varied from 0.86 to 0.88 and the intrarater reliability varied from 0.87 to 0.96. For Greulich and Pyle skeletal age, the interrater reliability varied from 0.87 to 0.89 and the intrarater reliability varied from 0.91 to 0.95. CONCLUSIONS: Use of the Sanders multiplier and skeletal stages was more accurate than the Paley multiplier and skeletal age in this cohort. Use of the White-Menelaus formula and skeletal age was slightly more accurate in predicting femoral length and slightly less accurate in predicting tibial length compared with the Sanders multiplier. Intra- and interrater reliability were similar between Sanders skeletal stages and Greulich and Pyle atlas skeletal age. The White-Menelaus formula and skeletal age was the recommended method for predicting lower-extremity segment lengths at maturity and epiphysiodesis effect. Although easier to recall without referencing an atlas and not sex-specific, Sanders skeletal staging does not correspond directly to years of growth remaining, and thus cannot be used with the White-Menelaus formula. CLINICAL RELEVANCE: The Greulich and Pyle atlas to determine skeletal age and the White-Menelaus formula to determine growth remaining are reliable predictors of epiphysiodesis effect in the lower extremities.

Prevention of guanylyl cyclase-B dephosphorylation rescues achondroplastic dwarfism.

Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) or inactivating mutations in guanylyl cyclase-B (GC-B), also known as NPR-B or Npr2, cause short-limbed dwarfism. FGFR3 activation causes dephosphorylation and inactivation of GC-B, but the contribution of GC-B dephosphorylation to achondroplasia (ACH) is unknown. GC-B7E/7E mice that express a glutamate-substituted version of GC-B that cannot be inactivated by dephosphorylation were bred with mice expressing FGFR3-G380R, the most common human ACH mutation, to determine if GC-B dephosphorylation is required for ACH. Crossing GC-B7E/7E mice with FGFR3G380R/G380R mice increased naso-anal and long (tibia and femur), but not cranial, bone length twice as much as crossing GC-B7E/7E mice with FGFR3WT/WT mice from 4 to 16 weeks of age. Consistent with increased GC-B activity rescuing ACH, long bones from the GC-B7E/7E/FGFR3G380R/G380R mice were not shorter than those from GC-BWT/WT/FGFR3WT/WT mice. At 2 weeks of age, male but not female FGFR3G380R/G380R mice had shorter long bones and smaller growth plate hypertrophic zones, whereas female but not male GC-B7E/7E mice had longer bones and larger hypertrophic zones. In 2-week-old males, crossing FGFR3G380R/G380R mice with GC-B7E/7E mice increased long bone length and hypertrophic zone area to levels observed in mice expressing WT versions of both receptors. We conclude that preventing GC-B dephosphorylation rescues reduced axial and appendicular skeleton growth in a mouse model of achondroplasia.

Systematic Isolation of Key Parameters for Estimating Skeletal Maturity on Knee Radiographs.

BACKGROUND: The ability to estimate skeletal maturity using a knee radiograph would be useful in anterior cruciate ligament (ACL) injuries and limb-length discrepancy in immature patients. Currently, a quick, accurate, and reproducible method is lacking. METHODS: Serial knee radiographs made 3 years before to 2 years following the chronologic age associated with 90% of final height (an enhanced skeletal maturity gold standard compared with peak height velocity) were analyzed in 78 children. The Pyle and Hoerr (PH) knee method was simplified by developing discrete stages for the distal part of the femur, the proximal part of the tibia, the proximal part of the fibula, and the patella. The Roche-Wainer-Thissen (RWT) knee method was simplified from the 36 original parameters to 14 parameters by removing parameters that were poorly defined, were not relevant to the peripubertal age range, were poorly correlated with 90% final height, or were poorly reliable on a 20-radiograph pilot analysis. We also compared the recently described central peak value (CPV) of the distal part of the femur. The Greulich and Pyle (GP) left-hand bone age was included for comparison. RESULTS: In this study, 326 left knee radiographs from 41 girls (age range, 7 to 15 years) and 37 boys (age range, 9 to 17 years) were included. Stepwise linear regression showed higher correlation in predicting years from 90% final height using the modified RWT and demographic characteristics (R2 = 0.921) compared with demographic characteristics alone (R2 = 0.840), CPV and demographic characteristics (R2 = 0.866), GP and demographic characteristics (R2 = 0.899), and PH and demographic characteristics (R2 = 0.902). Seven parameters were excluded from the RWT and demographic characteristics model using stepwise linear regression and generalized estimating equations analysis, leaving 7 parameters (2 femoral, 4 tibial, and 1 fibular) in the final model. Compared with RWT and demographic characteristics (R2 = 0.921), there were minimal incremental increases by adding CPV (R2 = 0.921), GP (R2 = 0.925), or PH (R2 = 0.931). CONCLUSIONS: This large analysis of knee skeletal maturity systems isolated 7 discrete radiographic knee parameters that theoretically outperform the GP bone age in estimating skeletal maturity. CLINICAL RELEVANCE: We present a modified knee skeletal maturity system that can potentially preclude the need for additional imaging of the hand and wrist in reliably estimating skeletal maturity.

Cadmium exposure negatively affects the microarchitecture of trabecular bone and decreases the density of a subset of sympathetic nerve fibers innervating the developing rat femur.

Cadmium (Cd) is toxic to the skeletal system resulting in bone loss and pain. We aimed at determining the effect of chronic Cd exposure on bone density and microarchitecture along with changes in the density of a subset of sensory and sympathetic nerve fibers innervating the developing rat femur. Newborn male Wistar rats were injected daily for 49 days with CdCl2 (1 mg/kg i.p.) or saline solution (control group). At the day of sacrifice, levels of Cd in the right femur, liver and kidney were determined by atomic absorption spectrophotometry. Additionally, microCT followed by immunohistochemical analyses were performed in the left femur. Results showed Cd accumulation in trabecular bone neared levels seen in liver and kidney. Cd concentration in cortical bone was significantly lower versus trabecular bone. MicroCT analysis revealed that Cd-exposed rats had a significant decrease in trabecular bone parameters at the distal femoral metaphysis; however, most of the cortical bone parameters were not significantly affected. Cd-exposed rats showed a significant loss of TH+ sympathetic nerve fibers, but not of CGRP+ sensory nerve fibers, at the level of bone marrow of the femoral diaphysis as compared to control rats. This study shows that Cd negatively affects bone density and microarchitecture of trabecular bone and decreases the density of sympathetic nerve fibers innervating rat femur. Future studies are warranted to determine the toxigenic mechanisms of Cd on sympathetic nerves and how sympathetic denervation influences bone loss in animals exposed to Cd.

Fatores associados a medidas biométricas fetais pequenas para idade gestacional no Estudo MINA-Brasil / Factors associated with small-for-gestational-age fetal biometric measurements in the MINA-Brazil Study

Introdução - As elevadas taxas de mortalidade neonatal e a prevalência de bebês nascidos pequenos para idade gestacional (PIG) ainda apresentadas por regiões de baixa e média renda indicam a necessidade de investigação sobre fatores que influenciam o crescimento fetal. Medidas biométricas fetais

Introduction Elevated rates of neonatal mortality and small-for-gestational-age (SGA) babies in low- and middle-income regions indicate the need to investigate factors associated with fetal growth. Fetal biometric measurements below the 10th percentile for gestational age (GA) reflect failure in achieving growth potential and provide opportunities for prenatal interventions. Objective To investigate factors associated with fetal biometric measurements below the 10th percentile assessed at early third trimester among pregnant women in the MINA-Brazil study. Methods This was a prospective analysis of pregnant women living in the urban area of Cruzeiro do Sul (AC), followed up since the antenatal period. Screening of participants took place from February 2015 to January 2016. A sociodemographic and health history interview was carried out along with two clinical assessments, scheduled between the second and third trimesters of pregnancy, to collect data on lifestyle factors and complications during pregnancy, anthropometric evaluation, blood collection, and ultrasound scan assessing fetal biometric measurements of head circumference (HC), abdominal circumference (AC) and femoral length (FL). Poisson regression models with hierarchical selection of variables were fitted for factors associated with occurrence of fetal measurements below the 10th percentile at early third trimester. Prevalence ratios (PR) and 95% confidence intervals (95%CI) were estimated. Results Among 426 participants (mean age 25 years (SD 6.4) and gestational age 27.8 weeks (SD 1.7)), 11.3%, 8.9% e 9.4% had fetuses with HC, AC, FL below the 10th percentile at early third trimester. Fetal biometric measurements below the 10th percentile were negatively associated with higher maternal education level, which denoted over 50% of protection (HC: PR 0.47, 95%CI 0.28; 0.81; AC: PR 0.48, 95%CI 0.26; 0.87; and FL: PR 0.48, 95%CI 0.27; 0.86). Adjusted for maternal education level, nulliparity (PR 1.94, 95%CI 1.10; 3.43), higher pre-gestational body mass index (BMI) (PR 1.06, 95%CI 1.01; 1.11), and pre-gestational alcohol consumption (PR 1.80, 95%CI 0.98; 3.30) were associated with HC measurements below the 10th percentile. Maternal height (p for trend 0.039) and pre-gestational alcohol consumption (PR 2.55, 95%CI 1.31; 4.96) were also associated with AC measurements below the 10th percentile. Association between higher average screen time per day during antenatal follow-up and FL measurements below the 10th percentile were observed as well (p for trend 0.031). Higher maternal education level, which may provide better material and non-material conditions, seems to protect fetal growth from failure to reach potential fetal size for GA. Positive associations observed with obstetric and antenatal conditions may be mediated by biological factors or gestational dysfunctions to incur in fetal measurements below the 10th percentile. Conclusion The occurrence of fetal biometric measurements below the 10th percentile for GA and their associated factors corroborate pre-pregnancy and antenatal care improvements anchored in equity policies, and for new strategies prior to birth that optimize the window of opportunity in the first thousand days of life.

In vitro and in vivo study of naturally derived alginate/hydroxyapatite bio composite scaffolds.

Biogenic bioceramics scaffolds are receiving considerable attention for bone restoration applications. Compared with scaffolds of chemical origin, biogenic scaffolds exhibit greater biocompatibility and enhanced bioactive features. In the present study, porous biogenic hydroxyapatite (bHA) was prepared via a polymeric infiltration route and was subsequently coated with alginate to produce alginate/biogenic hydroxyapatite (Alg/bHA) composites. Alginate was used to enhance the mechanical properties as well as the bioactivity and biodegradability of the HA scaffolds. A coating of 3%w/v alginate applied for 10 min was found to result in the best coating for the HA porous scaffolds. The in vitro study demonstrated that the prepared composites had acceptable bioactivity and biodegradability characteristics. The histological study in femur bone of rats indicated that the 3Alg/HA scaffolds capable of supporting both endochondral and intramembranous bone formation. The defect was fully regenerated and mostly filled with the mature lamellar bone after 6 months, with Ca/P atomic ratio similar to the rat's normal bone. The studied scaffolds provide a promising therapeutic option to enhance local bone healing because they do not damage liver or kidney functions and do not induce carcinogenic or inflammatory effects. Accordingly, 3Alg/HA scaffolds are recommended for the tissue engineering applications.

Discoidin Domain Receptor 1 Regulates Runx2 during Osteogenesis of Osteoblasts and Promotes Bone Ossification via Phosphorylation of p38.

Discoidin domain receptor 1 (Drd1) is a collagen-binding membrane protein, but its role in osteoblasts during osteogenesis remains undefined. We generated inducible osteoblast-specific Ddr1 knockout (OKOΔDdr1) mice; their stature at birth, body weight and body length were significantly decreased compared with those of control Ddr1f/f-4OHT mice. We hypothesize that Ddr1 regulates osteogenesis of osteoblasts. Micro-CT showed that compared to 4-week-old Ddr1f/f-4OHT mice, OKOΔDdr1 mice presented significant decreases in cancellous bone volume and trabecular number and significant increases in trabecular separation. The cortical bone volume was decreased in OKOΔDdr1 mice, resulting in decreased mechanical properties of femurs compared with those of Ddr1f/f-4OHT mice. In femurs of 4-week-old OKOΔDdr1 mice, H&E staining showed fewer osteocytes and decreased cortical bone thickness than Ddr1f/f-4OHT. Osteoblast differentiation markers, including BMP2, Runx2, alkaline phosphatase (ALP), Col-I and OC, were decreased compared with those of control mice. Ddr1 knockdown in osteoblasts resulted in decreased mineralization, ALP activity, phosphorylated p38 and protein levels of BMP2, Runx2, ALP, Col-I and OC during osteogenesis. Overexpression and knockdown of Ddr1 in osteoblasts demonstrated that DDR1 mediates the expression and activity of Runx2 and the downstream osteogenesis markers during osteogenesis through regulation of p38 phosphorylation.

Lipoteichoic Acid Accelerates Bone Healing by Enhancing Osteoblast Differentiation and Inhibiting Osteoclast Activation in a Mouse Model of Femoral Defects.

Lipoteichoic acid (LTA) is a cell wall component of Gram-positive bacteria. Limited data suggest that LTA is beneficial for bone regeneration in vitro. Thus, we used a mouse model of femoral defects to explore the effects of LTA on bone healing in vivo. Micro-computed tomography analysis and double-fluorochrome labeling were utilized to examine whether LTA can accelerate dynamic bone formation in vivo. The effects of LTA on osteoblastogenesis and osteoclastogenesis were also studied in vitro. LTA treatment induced prompt bone bridge formation, rapid endochondral ossification, and accelerated healing of fractures in mice with femoral bone defects. In vitro, LTA directly enhanced indicators of osteogenic factor-induced MC3T3-E1 cell differentiation, including alkaline phosphatase activity, calcium deposition and osteopontin expression. LTA also inhibited osteoclast activation induced by receptor activator of nuclear factor-kappa B ligand. We identified six molecules that may be associated with LTA-accelerated bone healing: monocyte chemoattractant protein 1, chemokine (C-X-C motif) ligand 1, cystatin C, growth/differentiation factor 15, endostatin and neutrophil gelatinase-associated lipocalin. Finally, double-fluorochrome, dynamic-labeling data indicated that LTA significantly enhanced bone-formation rates in vivo. In conclusion, our findings suggest that LTA has promising bone-regeneration properties.

Controlled Delivery of Curcumin and Vitamin K2 from Hydroxyapatite-Coated Titanium Implant for Enhanced in Vitro Chemoprevention, Osteogenesis, and in Vivo Osseointegration.

Successful repair of critical-sized tumor-resection defects, especially in load-bearing bones, still remains a major challenge in clinical orthopedics. Titanium (Ti) implants have been increasingly used in the past few decades because of titanium's suitable mechanical properties and biocompatibility; however, it shows insufficient integration with the surrounding bone. In this study, the plasma spray technique is utilized to form homogeneous hydroxyapatite (HA) coating on the surface of the Ti implant to enhance osseointegration at the tissue-implant interface. These coated implants are loaded with curcumin and vitamin K2 to introduce chemopreventive and osteogenesis ability via controlled release of these biomolecules. The synergistic effect of these two biomolecules showed enhanced in vitro osteoblast (hFOB) cell attachment and proliferation for 11 days. Moreover, these biomolecules showed lower in vitro osteosarcoma (MG-63) cell proliferation after 3, 7, and 11 days. An in vivo study was carried out to evaluate the bone bonded zone in a rat distal femur model at an early wound healing stage of 5 days. Modified Masson Goldner staining of the tissue-implant section showed improved contact between tissue and implant in dual drug-loaded HA-coated Ti implants compared to control implants. This work presents a successful fabrication of a mechanically competent functional Ti implant with the advantages of enhanced in vitro osteoblast proliferation, osteosarcoma inhibition, and in vivo osseointegration, indicating the potential for load-bearing bone-defect repair after tumor resection.

Changes in Cartilage and Subchondral Bone of Femoral Trochlear Groove After Patellectomy in Growing Rabbits.

OBJECTIVE: To explore the effects of patellectomy on the bony and cartilaginous morphology of the trochlear groove in growing rabbits. METHODS: Forty-eight 4-week-old New Zealand white rabbits were randomly assigned to two groups. The control group underwent a sham surgical procedure, whereas the patellectomy group underwent patella excision surgery. Half of the rabbits in each group were sacrificed 3 months postoperatively; the rest were sacrificed 6 months postoperatively. Hematoxylin and eosin staining was performed on collected samples. Measurements included the bony and cartilaginous sulcus angles of the trochlear groove. In addition, the thickness of the articular cartilage at the deepest sulcus position (central thickness) and at the mid-position of the medial and lateral facets was measured and compared between groups. RESULTS: Three months after surgery, histological images revealed significant differences between the control group and the patellectomy group in cartilaginous sulcus angle (144.2° ± 1.5° vs 151.9° ± 2.4°, respectively; P < 0.001). No obvious difference in bony sulcus angle was found between the groups. Six months after surgery, significant between-group differences were observed in cartilaginous sulcus angle (136.3° ± 2.5° in control group vs 160.7° ± 3.0° in patellectomy group, P < 0.001) and bony sulcus angle (136.2° ± 2.2° in control group vs 160.4° ± 2.6° in patellectomy group, P < 0.001). However, there were no significant intra-group differences between cartilaginous and bony sulcus angles in either group. Three months after surgery, significant between-group differences were detected in articular cartilage thickness at the three different positions (medial facet: 324.3 ± 14.0 µm in control group vs 391.7 ± 98.8 µm in patellectomy group, P = 0.029; central position: 362.1 ± 13.6 µm in control group vs 730.3 ± 76.8 µm in patellectomy group, P < 0.001; lateral facet: 324.6 ± 12.7 µm in control group vs 358.5 ± 38.7 µm in patellectomy group, P = 0.009). No between-group differences in cartilage thickness were found at 6 months. CONCLUSIONS: Abnormal mechanical stress (patellectomy) during a rabbit's development can cause flattening of the femoral trochlear cartilage, followed by changes in the subchondral osseous layer. Abnormal mechanical stress is a crucial factor in the development of trochlear groove dysplasia.

Rabbit growth plate morphology in temporary bilateral blocking / Morfología de la placa de crecimiento de conejos durante bloqueo bilateral temporario

Blocking of the growth plate (GP) using plates with screws (tension band plating) is a modern method used to correct deformities and moderate leg length discrepancy in growing children. Determining the duration of temporary bilateral blocking without the occurrence of irreversible changes of GP is of paramount importance important. Methods: Two-month-old Californian breed male rabbits (n=30) were exposed to bilateral blocking of the distal GP of the right femur locking plates with screws for 3, 5, and 7 weeks. The fixators were removed after 5 and 7 weeks in 18 rabbits and 3 weeks after that, animals were sacri!ced. The contralateral limb was used as a control. Histological, histomorphometric, and X-ray analyses were performed. Results: During GP blocking, its height gradually decreased. This decreased was more pronounced after 7 weeks. Destructive changes progressed with an increase in the blocking duration. Three weeks after discontinuation of the bilateral blocking that lasted 5 weeks, the height of the GP signi!cantly increased 1.2 times on the lateral side and 1.9 times on the medial side (p<0.001) compared to the control. When blocking was discontinued after 7 weeks, the structure of the GP was partially restored after 3 weeks, the height of GP signi!cantly increased 1.2 times on the lateral side, and 1.07 times on the medial side (p<0.01) compared to the control. Conclusion: Restoration of the structuralfunctional features of the GP after the removal of the plates depends on the duration of temporary bilateral blocking, which must be taken into account in the clinical setting. (AU)

El bloqueo de la placa de crecimiento (PC) utilizando placas con tornillos (banda de tensión) es un método moderno utilizado para corregir deformidades y alteraciones moderadas en la longitud de las piernas en niños en crecimiento. Es de suma importancia determinar cuál debe ser la duración del bloqueo bilateral temporal sin que ocurran cambios irreversibles en la PC. Métodos: Conejos machos de raza californiana de dos meses de edad (n = 30) fueron expuestos al bloqueo bilateral de la PC distal colocando placas del fémur derecho con tornillos durante 3, 5 y 7 semanas. Los fijadores fueron retirados después de 5 y 7 semanas en 18 de los conejos, y 3 semanas después los animales fueron sacrificados. La extremidad contralateral se utilizó como control. Se realizaron análisis histológicos, histomorfométricos y de rayos X. Resultados: Durante el bloqueo de la PC, su altura disminuyó gradualmente. Esta disminución fue más pronunciada después de 7 semanas. Los cambios destructivos se incrementaron a medida aumentaba la duración del bloqueo. Tres semanas después de la interrupción del bloqueo bilateral que duró 5 semanas, la altura de la PC aumentó significativamente 1.2 veces en el lado lateral y 1.9 veces en el lado medial (p <0.001) en comparación con el control. Conclusión: La restauración de las características funcionales estructurales de la PC después de la extracción de las placas depende de la duración del bloqueo bilateral temporal, lo que debería tenerse en cuenta en el tratamiento clínico de estas alteraciones. (AU)

The dysplastic trochlear sulcus due to the insufficient patellar stress in growing rats.

BACKGROUND: Developmental factors were assumed to be the key factors that influenced the morphology of femoral trochlea. This study investigated the effects of insufficient patellar stress after birth on the morphological development of the femoral trochlea. Effects of insufficient patellar stress on femoral trochlea were investigated using surgical induced patellectomy and patellar dislocation in growing rat model. METHODS: In this study, two experimental groups and one sham group (SG) were established. Thirty-six Wistar rats (female, 28 days of age) were randomly assigned to three groups. The patellectomy group (PG), rats underwent the patellectomy in this group. The dislocation group (DG), rats underwent the surgery-induced patellar dislocation. Histological staining (Safranin-O and fast green), Micro-computed tomographic (Micro-CT) analysis in two experimental endpoints (3, 12 weeks postoperatively) were selected to evaluate morphological changes of the femoral trochlea. RESULTS: Articular cartilage on the trochlear sulcus was remodeled at 3 weeks after the surgery, and degenerated at 12 weeks through the histological staining. The femoral trochlear angle (FTA) did not show a significant difference at 3 week between the experimental groups and the sham group (PG vs SG P = 0.38, DG vs SG p = 0.05), but the FTA was significantly increased in experimental groups at 12 weeks(PG vs SG P = 0.001, DG vs SG p = 0.005). The Bone volume density (BV/TV), Trabecular number (Tb.N) under the trochlea groove were significantly reduced at 3 weeks postoperatively in the experimental groups (PG vs SG p = 0.001, DG vs SG p = 0.002). No significant difference was found in BV/TV and Tb. N among the three groups at 12 weeks postoperatively. CONCLUSION: Surgical induced patellectomy and patellar dislocation leads to the dysplastic trochlear sulcus in growing rats. Besides the bone morphology of trochlear sulcus, the articular cartilage and subchondral trabecula under the trochlear sulcus were remodeled early stage after the surgery.

Guided Growth of the Proximal Femur for the Management of Hip Dysplasia in Children With Cerebral Palsy.

BACKGROUND: Progressive hip displacement is one of the most common and debilitating deformities seen in children with cerebral palsy (CP). The aim of this study was to evaluate the results of temporary medial hemiepiphysiodesis of the proximal femur (TMH-PF) using a transphyseal screw to control hip migration during growth in children with CP. METHODS: This was a retrospective study of children with CP and hip dysplasia, age 4 to 11 years and GMFCS levels III-V. There were 28 patients with 56 hips that underwent TMH-PF surgery between 2007 and 2010. Clinical and radiologic evaluation was performed preoperatively, at 6, 12, and 60 months following the index surgery. Acetabular index (AI), neck-shaft angle (NSA) and migration percentage (MP) were measured. All complications were recorded. RESULTS: All radiographic measurements were significantly improved at the final follow-up. Positive correlations were found between NSA, MP, and AI. Multiple regression analysis revealed that MP, time from surgery, and age were influenced by the decrease of the NSA. The femoral physis grew off the screw in 9 hips within 36 months. The screw head broke during attempted screw exchange in 1 hip. The remain cases (4 hips) were treated by placing a second screw parallel to the existing one. Finally, progressive subluxation occurred in 3 hips when the physis grew off the screw and were treated by skeletal reconstruction. CONCLUSIONS: TMH-PF was effective in controlling progressive subluxation of the hip in the majority of cases, obviating the need for major reconstructive surgery in these children with CP. LEVEL OF EVIDENCE: Level IV.

A comparative study on agarose acetate and PDLLA scaffold for rabbit femur defect regeneration.

The development of degradable polymer scaffolds is a key issue in bone regeneration. Poly(D, L-lactide) (PDLLA) and its derivatives have usually been applied to the construction of degradable scaffolds, but these scaffolds had problems with acidic degradation products and quick loss of mechanic strength during the later degradation, which usually led to scaffold collapse and cavity formation because of the slower rate of bone regeneration. In the present paper, a polysaccharide derivative, agarose acetate (AGA), was synthesized and a novel porous AGA scaffold was successfully developed through a salt-leaching process. The AGA scaffold had over 90% porosity without swelling in water, and compared to collapse and acidic products of PDLLA scaffold during degradation, the AGA scaffold maintained a stable morphology and a nearly neutral pH value over 18 months' degradation in PBS. A bone mesenchymal stem cells (BMSCs) adhesion and proliferation experiment showed that more cells adhered to the AGA scaffold than to the PDLLA scaffold. A subcutaneous implant test showed that the AGA scaffold slowly degraded and did not cause an inflammatory response surrounding the implantation lesion site. AGA scaffold was implanted into femur defects in New Zealand white rabbits to test its in vivo performance. Results indicated that the AGA scaffold accelerated the process of bone regeneration compared to the PDLLA group and, with time, new bone was formed from the margin toward the center of the scaffolds, and the scaffold left in place retained its porous structure without collapsing. Meanwhile, the AGA scaffold showed a low degradation rate and kept its shape during the in vivo degradation compared to the PDLLA scaffold. This performance could have the benefit of integrated regenerative bone being formed instead of cavities due to the quickly degraded scaffold disappearing. These results demonstrate that the AGA scaffold has significant potential in bone regeneration applications.

Guided Growth Improves Coxa Valga and Hip Subluxation in Children with Cerebral Palsy.

BACKGROUND: Spastic hip subluxation or dislocation that is associated with an excessive coxa valga deformity is a common pathologic condition in children with cerebral palsy (CP) that is often treated with large bone reconstructive procedures. Guided growth techniques (such as stapling, plate, or transphyseal screw) have been widely used to alter the growth axis in patients with a lower-limb deformity but only a few reports have described their use in patients with coxa valga deformities. QUESTIONS/PURPOSES: (1) Does guided growth surgery using a transphyseal screw combined with adductor tenotomy prevent progressive coxa valga deformity and lateral hip subluxation in children with CP? (2) What factors influence the correction of coxa valga deformity and the success of hip stabilization? (3) What complications were associated with this operation and how often did children treated with it undergo reoperation? METHODS: From 2012 to 2016, at our institution, three authors (H-CH, KNK, K-WW) retrospectively studied data on children with CP who underwent guided growth of the hip for progressive bilateral hip subluxation associated with coxa valga deformities. A single percutaneous screw was inserted across the inferomedial portion of proximal femoral physis in an AP view and centered along femoral neck in lateral view under fluoroscopy guidance. During the period, we treated 25 consecutive children with CP who had progressive hip subluxation with coxa valga deformities. The indications for surgery were migration percentage > 30% and head-shaft angle > 155° with at least 2 years growth remaining. Of those, 13 patients underwent guided growth alone, and 48% (12) underwent a combination of guided growth and adductor tenotomy. Of the 25 patients treated with this approach, 96% (24) were available for follow-up with complete data at a minimum of 2 years follow-up (mean 50 months; range 25 to 72). All children (17 boys and seven girls; 48 hips) underwent surgery at a mean age of 8 years (range 5 to 12). With regard to the gross motor function classification system, three patients were Level 1, four patients were Level II, seven patients were Level III, seven were Level IV, and three were Level V. Radiographic parameters including the head-shaft angle, Hilgenreiner's epiphyseal angle, acetabular index, and Reimer's migration percentage were assessed before surgery and at the latest follow-up examination by one author (H-CH). Complications and reoperations were assessed by chart review. During the period in question, we generally offered secondary reconstructive surgery to patients who underwent a guided growth procedure once their subluxation progressed. RESULTS: With the data available, the coxa valga and lateral hip subluxation improved in terms of the reduction of head-shaft angle by a mean of 13° ± 7° (95% CI 11 to 15; p < 0.001) and the reduction of the migration percentage by 10% ± 11% (95% CI 7 to 13; p < 0.001). After controlling for potentially confounding variables like gender, gross motor function classification system, Hilgenreiner's epiphyseal angle and acetabular index, we found that longer follow-up duration (r = 0.234; p < 0.001) and a smaller preoperative migration percentage (r = -0.258; p = 0.004) were associated with larger changes in the head-shaft angle. In terms of complications, we found that the proximal femoral physis grew off the screw tip in 44% (21 of 48 hips) at a mean of 28 months. Among these, 31% of hips (15 of 48) in 33% of patients (eight of 24) underwent replacement with a longer screw. Among the 17% of hips (eight of 48) in 21% of patients (five of 24) who had progressive lateral subluxation and underwent secondary reconstructive surgery, we found that their preoperative acetabular index was higher (mean 29° versus 21°; p < 0.001), as was their head-shaft angle (mean 166° versus 162°; p = 0.045), and migration percentage (mean 54% versus 36 %; p < 0.001). CONCLUSIONS: Although guided growth with single transphyseal screw did not create as large a degree of varus as proximal femoral osteotomy, it did stabilize the hip in children with cerebral palsy with migration percentage less than 50% in our series. It is a simple procedure that can be of benefit to children with cerebral palsy with unstable hip. Reoperation in patients where the physis has grown off the screw tip can be a problem; fortunately, it is a rather minor procedure to replace with a longer screw. LEVEL OF EVIDENCE: Level III, therapeutic study.

A nutraceutical composition containing diosmin and hesperidin has osteogenic and anti-resorptive effects and expands the anabolic window of teriparatide.

A combination of diosmin and hesperidin (9:1 ratio) is marketed as a dietary supplement/nutraceutical for cardiovascular health. We studied the skeletal effect of this combination (90% diosmin and 10% hesperidin, henceforth named as DH). We showed that a) in rats with femur osteotomy, DH stimulated callus bone regeneration, b) in growing rats, DH promoted peak bone mass achievement and c) in OVX rats rendered osteopenic, DH completely restored femur trabecular bones and strength along with the increases in surface referent bone formation and serum osteogenic marker. Furthermore, DH suppressed bone resorption in OVX rats as well as in OVX rats treated with teriparatide (human parathyroid hormone 1-34) but did not affect the osteoanabolic effect of teriparatide. These data suggested that DH could prolong the anabolic window of teriparatide. To understand the mechanism of DH action, we performed pharmacokinetic studies and observed that upon its oral administration the only circulating metabolites was diosmetin (the aglycone form of diosmin) while none of the two input flavanones were detectable. Accordingly, subsequent experiments with diosmetin revealed that it was a selective estrogen receptor-ß agonist that stimulated osteoblast differentiation and suppressed sclerostin the anti-osteoblastogenic Wnt antagonist. Taken together, our study defined a positive skeletal effect of DH.

Distal femoral hemiepiphysiodesis with screws and suture versus 8-plate for the treatment of genu valgum in children.

INTRODUCTION: There are different techniques for gradual correction of angular deformities in lower limbs. The use of screws and non-absorbable filament have been described as an effective alternative for transitory hemiepiphysiodesis in pediatric population. HYPOTHESIS: In pediatric population with genu valgum there are no differences in outcome between hemiepiphysiodesis, using screws and non-absorbable filament (SNAF) versus 8-plate. METHODS: Retrospective evaluation, 44 knees in 22 patients younger than 15 years, with idiopathic genu valgum, were operated on. One group (20 knees) was operated on with 8-plate technique and another group (24 knees) was operated on with SNAF technique. Initial and final intermalleolar distance (IMD) and mechanical lateral distal femoral angle (mLDFA) were compared, registering complications for each group. Mann-Whitney test was used for statistics, with significance value <0.05. RESULTS: All patients achieved the expected mechanical axis correction. IMD and mLDFA significatively improved. There were no significant differences in magnitude and speed of correction when comparing the two techniques. Only one SNAF patient had a minor perioperative complication. DISCUSSION: This report compares postoperative results between SNAF and 8-plate technique for correction of angular deformities in lower limbs. In this series of patients, significant clinical and radiological changes were observed between the initial and final values using both techniques, with no significant differences between them. Our group proposes the SNAF technique as an efficient, simple and cost-effective alternative to the traditional 8-plate technique, for the treatment of idiopathic genu valgum in children. LEVEL OF EVIDENCE: III, retrospective comparative study.

Guided growth with tension band plate or definitive epiphysiodesis for treatment of limb length discrepancy?

BACKGROUND: It is not exactly known whether guided growth or definitive epiphysiodesis techniques are superior in treating limb length discrepancy (LLD). The purpose of the present study was therefore to find out if definitive epiphysiodesis is associated with more powerful LLD correction than tension band plate epiphysiodesis. METHODS: Pediatric patients with LLD treated either with tension band plating as a guided growth technique (temporary epiphysiodesis) or a percutaneous drilling technique (definitive epiphysiodesis) around the knee and a minimum follow-up of 12 months were included in this retrospective study. Radiographic measurements were performed by two independent reviewers. The reduction in side difference between preoperative radiographs and last follow-up was calculated and compared between surgical techniques. RESULTS: Thirty-eight patients (mean age 13.6 years) were included, 17 treated with temporary and 21 with definitive epiphysiodesis. Average follow-up was at 578 days. The reduction of the LLD in 12 months was 5.7 mm in patients treated with temporary epiphysiodesis and 8.4 mm with definitive epiphysiodesis, respectively (p = 0.22). In both groups, LLD could be statistically significantly reduced after 12 and 24 months. Definitive epiphysiodesis had a lower revision rate (4.8% vs. 17.6%). Intra- and interobserver reliability of the measurements was excellent. CONCLUSIONS: As in earlier studies supposed, temporary epiphysiodesis with tension band plating seems to correct LLD less powerful compared to definitive percutaneous epiphysiodesis. However, in the present study, the differences of LLD correction were not statistically significant. We do not recommend the use of tension band plates for LLD correction due to inferior correction with higher complication and revision rate.

Excision of Physeal Bars of the Distal Femur, Proximal and Distal Tibia Followed to Maturity.

OBJECTIVE: In the 50 years since a premature partial physeal arrest (a physeal bar) was first excised from an epiphysis there have been no large in-depth studies reporting the results in patients followed to skeletal maturity. This paper reports the results of physeal bar resection surgery in a group of patients followed to skeletal maturity, documenting the restored growth of the affected physis, the affected bone, and the final limb-length discrepancy. METHODS: Forty-eight patients underwent physeal bar resection of the distal femur (21), proximal tibia (9), and distal tibia (18) by 1 surgeon (H.A.P.) from 1968 through 1996, and were followed prospectively to skeletal maturity with clinical and radiologic examinations. Factors such as sex, age at time of injury, etiology of the bar, physeal bar location and size, age at time of bar excision, interposition material, and additional surgical procedures were analyzed with respect to physis, bone, and limb growth following bar resection. RESULTS: The mean growth for the entire bone following physeal bar excision was 7.6 cm for the distal femur, 4.7 cm for the proximal tibia, and 7.5 cm for the distal tibia, compared with growth in the contralateral control bone of 6.8 cm in the femur, 5.0 cm in the proximal tibia, and 7.8 cm in the distal tibia. The maximum bone growth following bar excision in a single patient was 21.3 cm for the distal femur, 10.3 cm for the proximal tibia, and 18.6 cm for the distal tibia. The mean limb-length discrepancy at maturity was -1.7 cm for the distal femur, -1.3 cm for the proximal tibia, and -1.1 cm for the distal tibia (all sites combined -1.4 cm). Fourteen patients (29%) had only the 1 bar excision with no other accompanying or subsequent surgery. Thirty-four patients (71%) had 1 to 4 accompanying or subsequent leg length or angular correcting procedures. CONCLUSIONS: Physeal bar excision to restore growth when applied to the appropriate patient is a useful, rewarding procedure, reducing the number of surgical limb length equalizing procedures. It is a demanding surgical procedure and requires diligent and careful follow-up until maturity. Additional limb length equalizing surgery is frequently needed. LEVEL OF EVIDENCE: Case series, level IV.