Rapid Bone Growth Research Articles

Mid- and long-term effectiveness of total hip arthroplasty with Ribbed femoral stem prosthesis in 354 cases

To evaluate the mid- and long-term effectiveness of total hip arthroplasty (THA) with Ribbed femoral stem prosthesis. A clinical data of 354 patients (384 hips) with hip disease who underwent THA with Ribbed femoral stem prostheses between October 2006 and May 2016 was retrospectively analyzed. There were 171 males and 183 females, with an average age of 53.4 years (range, 20-82 years). There were 324 cases of single hip and 30 cases of bilateral hips. The cause of THA included the avascular necrosis of the femoral head in 151 cases (159 hips), hip osteoarthritis in 134 cases (136 hips), rheumatoid arthritis in 43 cases (43 hips), ankylosing spondylitis in 20 cases (40 hips), and trauma in 6 cases (6 hips). The Harris score of total 354 patients before operation was 42.34±8.89. Harris scores were used to evaluate hip function after operation. X-ray films were used to determine the length of the lower limb, the radiolucent line on the femur side, the stability of the prosthesis, and the occurrence of stress shielding. The incisions healed by first intention. All patients were followed up 2-11 years with an average of 7.4 years. The Harris score at last follow-up was 80.52±7.61, which significantly increased when compared with preoperative score ( t=134.804, P=0.000). Two cases (2 hips) of prosthetic infections, 3 cases (3 hips) of prothesis loosening, and 4 cases (4 hips) of periprosthetic fractures, and 48 cases (48 hips) of mild to moderate thigh pain occurred after operation. X-ray films showed 76 cases (78 hips) with radiolucent lines on the femur side and stress shielding. According to the Engh's method, there were 364 hips of bone ingrowth, 15 hips of fibrosis ingrowth, and 5 hips of prosthesis instability. The femoral stem subsidence occurred in 25 cases (25 hips), and the difference in leg length discrepancy was more than 10 mm in 5 patients. THA with Ribbed femoral stem prosthesis can achieve satisfactory effectiveness with good initial stability and rapid bone growth. The incidence of stress shielding is relatively high, but the stress shielding has no significant impact on the mid- and long-term survival rate and effectiveness of femoral prosthesis.

Study on the morphology and mineralization of the tibia in meat ducks from 1 to 56 d.

The objective of this current study was to characterize the basic physiological data on morphological and mineralized properties of the tibia from 1 to 56 days, as well as the interrelationships of body weight (BW) and bone traits for meat ducks. A total of 176 1-d-old ducks was allocated into eight pens and fed with the same diet until the age of 56 d. Eight birds (1 ducks/pen) were randomly selected weekly for measuring BW and tibia characteristics. The BW of duck was increased with age throughout the whole study. Tibial length and width rapidly grew from 1 to 35 d, when it leveled off. The fat-free weight, ash, calcium (Ca) and phosphorus (P) content of tibia increased rapidly from 1 to 42 d and reached its plateau from 42 d onward. Tibial density and tibia-breaking strength increased in a regular manner with age until 42d. Serum alkaline phosphatase activity was higher between 1 to 7 d in the duck. Regression and ontogenetic scaling analysis showed the age of maximal growth rate in tibia dimension and mineralization was earlier than that in BW; when compared with BW, tibial fat-free weight and tibia-breaking strength increased isometrically, tibia length displayed a negative allometry, and tibial width showed a positive allometric growth. Results indicate that the tibia displayed rapid bone growth (1 to 35 d) and mineralization (1 to 42 d), and alkaline phosphatase (ALP) plays a critical role in the early stage of tibia mineralization of meat duck. Intensive selection for growth rate in ducks has resulted in tibial morphology changes, which represents an interesting compromise of adaptation for increasing BW.

MAPPING COMPRESSIVE AND TENSILE STRAINS OF THE PATELLAR TENDON IN OSGOOD-SCHLATTER DISEASE USING ULTRASOUND ELASTOGRAPHY

Background Osgood-Schlatter Disease (OSD) impacts millions of young athletes every year, yet its biomechanical etiology remains unclear. It’s been postulated that increased growth velocity in children elevates tension within the patellar tendon, placing distal strain on the tibial tubercle, causing anterior knee pain, but this process has not been previously elucidated. The purpose of this study was to evaluate axial tensile and transverse compressive strains in adolescent patellar tendons during exercise to identify differences between those with and without OSD using a cumulative strain, ultrasound elastography measurement method [REF: Chimenti et al 2016]. Methods Axial tensile and transverse compressive strains of the patellar tendon in eight adolescents with OSD and ten adolescents without OSD were quantified from ultrasound elastography images. Multiaxial strains of the patellar tendon were assessed as the participant performed two different exercises: 1) participant seated with leg fully extended, participant bends knee, followed by a return to initial extended position; (2) participant standing performs a squat and then returns to initial standing position. Participants’ disease severity was clinically assessed using the VISA-P and Cincinnati knee scale. Results Mean age was 13.1 years (+/- 2.7), 39% were male (63% of OSD group). There was no statistically significant difference in patellar tendon tensile strains during the seated knee flexion and squat positions between groups (p = 0.99, p = 0.83 respectively). The OSD group had significantly less tendon compression compared to the non-OSD group during both the knee flexion (p <0.01), and squat exercises (p <0.05). Conclusions/Significance Adolescents with OSD had lower transverse compressive strains in the patellar tendon as compared to adolescents without OSD. In contrast, tensile strains were not increased in children with OSD. These findings appear to contradict the tension hypothesis postulating that OSD is caused by increased patellar tendon axial tension associated with rapid bone growth, Instead, impingement from the tibia leading to transverse tendon compression may lead to an adaptive stiffing the patellar tendon, However, further research is needed to confirm this hypothesis. While OSD is a common cause of knee pain in growing athletes that frequently leads to loss in participation, its etiology is unclear, making development of effective treatment approaches difficult. This study highlights differences in multiaxial patellar tendon strains in adolescents with OSD which may help direct future research on management strategies.

Evaluation of Tolerable Upper Intake Levels for Vitamin D in Children and Adolescents

In 2012, the European Food Safety Authority (EFSA) suggested a tolerable upper intake level (UL) for vitamin D at 100 µg/day for adults based on the risk of hypercalcaemia. EFSA concluded that consumption of up to 50 µg/day does not lead to hypercalcaemia in children and adolescents (10-17 years). Furthermore, EFSA stated that there is no reason to assume that children and adolescents in the phase of rapid bone formation and growth have a lower tolerance for vitamin D compared to adults, and a UL of 100 µg/day for adolescents aged 11-17 years and 50 µg/day in children 1-10 years, taking the smaller body size into account, was proposed.
 The Norwegian Food Safety Authority (NFSA) is currently revising the national regulation of maximum limits in food supplements (not yet harmonised in the European Economic Area (EEA)), including maximum limits for vitamin D. NFSA has therefore requested the Norwegian Scientific Committee for Food Safety (VKM) to evaluate the assumption in the EFSA opinion that children and adolescents can tolerate the same amount of vitamin D as adults due to rapid bone formation and growth. In children and adolescents with lower weight than adults, this assumption actually implies that adolescents can tolerate more vitamin D per kg body weight than adults. VKM is therefore requested to evaluate if there is scientific evidence that a UL at 50 µg/day for children (1-10 years) and 100 µg/day for adolescents (11-17 years) is safe.
 The present statement is prepared by members of the Panel on Nutrition, Dietetic Products and Novel Food and Allergy in VKM.
 Three literature searches were performed to find new relevant studies investigating high intakes of vitamin D in children and adolescents and the role of vitamin D in bone formation and growth.
 No studies supporting a higher tolerance to vitamin D in children and adolescents due to rapid bone formation and growth were retrieved in the literature search. Moreover, there is apparently no firm association between bone formation and vitamin D levels in children during their growth period into adolescence and adulthood. 
 No studies investigating high intakes of vitamin D in children 1-10 years were found. Furthermore, no studies that have examined safety issues and/or adverse effects of vitamin D supplementation in doses above 50 µg/day in adolescents were identified. It can therefore not be concluded that the UL at 50 µg/day in children (1-10 years) and 100 µg/day in adolescents (11-17 years) is safe.
 In the 2002 report from European Scientific Committee on Food (SCF), a UL was set at 25 µg/day for children aged 2-10 years, and 50 µg/day for adolescents aged 11-17 years (corresponding to the UL for adults at that time). To the best of knowledge no serious, harmful effects have been reported for these doses of vitamin D.

Micrornas at the Interface between Osteogenesis and Angiogenesis as Targets for Bone Regeneration.

Bone formation and regeneration is a multistep complex process crucially determined by the formation of blood vessels in the growth plate region. This is preceded by the expression of growth factors, notably the vascular endothelial growth factor (VEGF), secreted by osteogenic cells, as well as the corresponding response of endothelial cells, although the exact mechanisms remain to be clarified. Thereby, coordinated coupling between osteogenesis and angiogenesis is initiated and sustained. The precise interplay of these two fundamental processes is crucial during times of rapid bone growth or fracture repair in adults. Deviations in this balance might lead to pathologic conditions such as osteoarthritis and ectopic bone formation. Besides VEGF, the recently discovered important regulatory and modifying functions of microRNAs also support this key mechanism. These comprise two principal categories of microRNAs that were identified with specific functions in bone formation (osteomiRs) and/or angiogenesis (angiomiRs). However, as hypoxia is a major driving force behind bone angiogenesis, a third group involved in this process is represented by hypoxia-inducible microRNAs (hypoxamiRs). This review was focused on the identification of microRNAs that were found to have an active role in osteogenesis as well as angiogenesis to date that were termed “CouplingmiRs (CPLGmiRs)”. Outlined representatives therefore represent microRNAs that already have been associated with an active role in osteogenic-angiogenic coupling or are presumed to have its potential. Elucidation of the molecular mechanisms governing bone angiogenesis are of great relevance for improving therapeutic options in bone regeneration, tissue-engineering, and the treatment of bone-related diseases.

The roles of magnesium in the mineral metabolism of biological apatite for the treatment of arthritis inspired by the deer antler

Nowadays, the treatment of osteoarthritis (OA), a highly prevalent joint disorder, remains a medical challenge because of the lack of understanding of its pathogenesis. In this work, we developed an alternative strategy of OA treatment using magnesium-based materials as potential therapeutic agent towards subchondral bone remodeling. We selected deer antlers as the animal model where calcification behaviors could provide interesting references for the rapid and reproducible endochondral bone growth. Extremely high content of Mg was detected in the antler, which was able to affect the evolutions of biological apatite. Herein, octacalcium phosphate (OCP) and amorphous calcium phosphate (ACP), which are critically involved in the calcification process, were respectively synthesized under the Mg-containing conditions to understand the role of Mg in the evolution of biological apatite. Results showed that the substitution of Mg2+ at lower contents stabilized OCP and ACP, while higher contents of Mg inhibited the formation of both phases. The size of both calcium phosphates was also altered significantly by the addition of Mg. The results of cell culture indicated that excess Mg notably accelerated the secretion of extracellular matrix and inhibited the mineralization of chondrocyte matrix. Hence, utilization of Mg-based materials in subchondral bone was supposed to provide a potential therapeutic approach to treat the OA by inhibiting subchondral of ossification process.

A cross-sectional study on the mechanical properties of the Achilles tendon with growth.

This study aimed to elucidate growth pattern of mechanical properties of the Achilles tendon and to examine if imbalance between growth of bone and muscle-tendon unit occurs during adolescence. Fourteen elementary school boys, 30 junior high school boys, 20 high school boys and 15 male adults participated in this study. Based on estimated age at peak height velocity (PHV), junior high school boys were separated into two groups (before or after PHV). An ultrasonography technique was used to determine the length, cross-sectional area, stiffness and Young's modulus of Achilles tendon. In addition, the maximum strain in "toe region" (strainTP) was determined to describe the balance between growth of bone and muscle-tendon unit. No group difference was observed in length, cross-sectional area and strainTP among the groups. However, stiffness and Young's modulus in after PHV groups were significantly higher than those of elementary school boys and before PHV groups(p ≤ 0.05). These results indicate that mechanical properties of Achilles tendon change dramatically at and/or around PHV to increased stiffness. The widely believed assumption that muscle-tendon unit is passively stretched due to rapid bone growth in adolescence is not supported.

Cortical and trabecular morphology is altered in the limb bones of mice artificially selected for faster skeletal growth

Bone strength is influenced by mineral density and macro- and microstructure. Research into factors that contribute to bone morphology and strength has focused on genetic, environmental and morphological factors (e.g., body mass index), but little is known regarding the impact of rates of skeletal elongation on adult skeletal morphology and strength. Using micro-CT, we examined the impact of rates of skeletal elongation on bone cortical and trabecular morphology, and on rates of estrogen-dependent bone loss in the tibia in CD-1 mice, and in mice with accelerated skeletal growth (Longshanks). Groups of adult mice (n = 7/group) were subjected to ovariectomy or sham surgeries, scanned for 6 weeks, and indices of bone morphology were collected. Results show that Longshanks mice had significantly less trabecular bone at skeletal maturity, characterized by fewer, thinner trabeculae, and furthermore lost trabecular bone more slowly in response to ovariectomy. Artificial selection for rapid skeletal growth relative to somatic growth thus had a significant impact on trabecular bone morphology in Longshanks. Our data do not unequivocally demonstrate a causal relationship between rapid bone growth and reduced trabecular bone quality, but suggest that rapid linear bone growth may influence the risk of cancellous bone fragility.

Sex-Dependent, Osteoblast Stage-Specific Effects of Progesterone Receptor on Bone Acquisition.

The role of the progesterone receptor (PR) in the regulation of sexual dimorphism in bone has yet to be determined. Here we utilized genetic fate mapping and Western blotting to demonstrate age-dependent PR expression in the mouse femoral metaphysis and diaphysis. To define sex-dependent and osteoblast stage-specific effects of PR on bone acquisition, we selectively deleted PR at different stages of osteoblast differentiation. We found that when Prx1-Cre mice were crossed with PR floxed mice to generate a mesenchymal stem cell (MSC) conditional KO model (Prx1; PRcKO), the mutant mice developed greater trabecular bone volume with higher mineral apposition rate and bone formation. This may be explained by increased number of MSCs and greater osteogenic potential, particularly in males. Age-related trabecular bone loss was similar between the Prx1; PRcKO mice and their WT littermates in both sexes. Hormone deficiency during the period of rapid bone growth induced rapid trabecular bone loss in both the WT and the Prx1; PRcKO mice in both sexes. No differences in trabecular bone mass was observed when PR was deleted in mature osteoblasts using osteocalcin-Cre (Bglap-Cre). Also, there were no differences in cortical bone mass in all three PRcKO mice. In conclusion, PR inactivation in early osteoprogenitor cells but not in mature osteoblasts influenced trabecular bone accrual in a sex-dependent manner. PR deletion in osteoblast lineage cells did not affect cortical bone mass. © 2017 American Society for Bone and Mineral Research.

Prophylactic pamidronate partially protects from glucocorticoid-induced bone loss in the mdx mouse model of Duchenne muscular dystrophy

Glucocorticoids are extensively used to treat patients with Duchenne muscular dystrophy because of their ability to delay muscle damage, prolong ambulation and extend life. However, use of glucocorticoids significantly increases bone loss, fragility and fractures. To determine if antiresorptive bisphosphonates could prevent the effects of glucocorticoids on bone quality, we used dystrophic mdx mice treated with the glucocorticoid prednisone during 8weeks of rapid bone growth from 5 to 13weeks of age and treated some mice with the bisphosphonate pamidronate during the first two weeks of prednisone administration. Prednisone reduced long bone growth, decreased cortical bone thickness and area and decreased the strength of the femurs. Pamidronate treatment protected mice from cortical bone loss but did not increase bone strength. The combination of prednisone and pamidronate inhibited remodeling of metaphyseal trabecular bone with large numbers of trabeculae containing remnants of calcified cartilage. Prednisone improved muscle strength in the mdx mice and decreased serum creatine kinase with evidence of improved muscle histology and these effects were maintained in mice treated with pamidronate.

In vivo radiometric analysis of glucose uptake and distribution in mouse bone.

Bone formation and remodeling occurs throughout life and requires the sustained activity of osteoblasts and osteoclasts, particularly during periods of rapid bone growth. Despite increasing evidence linking bone cell activity to global energy homeostasis, little is known about the relative energy requirements or substrate utilization of bone cells. In these studies, we measured the uptake and distribution of glucose in the skeleton in vivo using positron-emitting 18F-fluorodeoxyglucose ([18F]-FDG) and non-invasive, high-resolution positron emission tomography/computed tomography (PET/CT) imaging and ex vivo autoradiography. Assessment of [18F]-FDG uptake demonstrated that relative to other tissues bone accumulated a significant fraction of the total dose of the glucose analog. Skeletal accumulation was greatest in young mice undergoing the rapid bone formation that characterizes early development. PET/CT imaging revealed that [18F]-FDG uptake was greatest in the epiphyseal and metaphyseal regions of long bones, which accords with the increased osteoblast numbers and activity at this skeletal site. Insulin administration significantly increased skeletal accumulation of [18F]-FDG, while uptake was reduced in mice lacking the insulin receptor specifically in osteoblasts or fed a high-fat diet. Our results indicated that the skeleton is a site of significant glucose uptake and that its consumption by bone cells is subject to regulation by insulin and disturbances in whole-body metabolism.

Ameloblastin, an Extracellular Matrix Protein, Affects Long Bone Growth and Mineralization.

Matrix molecules such as the enamel-related calcium-binding phosphoprotein ameloblastin (AMBN) are expressed in multiple tissues, including teeth, bones, and cartilage. Here we have asked whether AMBN is of functional importance for timely long bone development and, if so, how it exerts its function related to osteogenesis. Adolescent AMBN-deficient mice (AMBN(Δ5-6) ) suffered from a 33% to 38% reduction in femur length and an 8.4% shorter trunk spinal column when compared with WT controls, whereas there was no difference between adult animals. On a cellular level, AMBN truncation resulted in a shortened growth plate and a 41% to 49% reduction in the number of proliferating tibia chondrocytes and osteoblasts. Bone marrow stromal cells (BMSCs) isolated from AMBN mutant mice displayed defects in proliferation and differentiation potential as well as cytoskeleton organization. Osteogenesis-related growth factors, such as insulin-like growth factor 1 (IGF1) and BMP7, were also significantly (46% to 73%) reduced in AMBN-deficient BMSCs. Addition of exogenous AMBN restored cytoskeleton structures in AMBN mutant BMSCs and resulted in a dramatic 400% to 600% increase in BMP2, BMP7, and Col1A expression. Block of RhoA diminished the effect of AMBN on osteogenic growth factor and matrix protein gene expression. Addition of exogenous BMP7 and IGF1 rescued the proliferation and differentiation potential of AMBN-deficient BMSCs. Confirming the effects of AMBN on long bone growth, back-crossing of mutant mice with full-length AMBN overexpressors resulted in a complete rescue of AMBN(Δ5-6) bone defects. Together, these data indicate that AMBN affects extracellular matrix production and cell adhesion properties in the long bone growth plate, resulting in altered cytoskeletal dynamics, increased osteogenesis-related gene expression, as well as osteoblast and chondrocyte proliferation. We propose that AMBN facilitates rapid long bone growth and an important growth spurt during the skeletogenesis of adolescent tooth-bearing vertebrates. © 2016 American Society for Bone and Mineral Research.

Stem cell infiltrated biomimetic inverse trabecular-pattered scaffolds accelerate bone growth during long segment repair in a sheep critical sized defect

Stem cell infiltrated biomimetic inverse trabecular-pattered scaffolds accelerate bone growth during long segment repair in a sheep critical sized defect

Effectiveness of mifamurtide in addition to standard chemotherapy for high-grade osteosarcoma: a systematic review.

Osteosarcoma mostly occurs during the period of rapid bone growth in children and adolescents as high-grade osteosarcomas. Current treatment recommended for high-grade non-metastatic and metastatic and/or relapsed osteosarcoma involves neoadjuvant multiagent conventional chemotherapy, followed by surgical resection of macroscopically detected tumor and postoperative adjuvant chemotherapy. However, residual micrometastatic deposits that develop following surgery have shown resistance to postoperative/adjuvant chemotherapy. Therefore, there is a critical need for more effective and innovative therapeutic approaches such as immune stimulatory agents. The most extensively studied immune stimulatory agent in the treatment of osteosarcoma is mifamurtide. The aim of this systematic review was to identify and synthesize the evidence on the effectiveness of mifamurtide in addition to standard chemotherapy on survival outcomes. To present the best available evidence on the treatment of high-grade non-metastatic and metastatic osteosarcoma with mifamurtide in addition to standard chemotherapy. All populations of patients regardless of age, gender or ethnicity with high-grade, resectable, non-metastatic and metastatic osteosarcoma based on histological diagnosis. This review focused on intravenous infusion of either of the pharmaceutical formulations of mifamurtide (MTP-PE or L-MTP-PE) in addition to standard chemotherapy, and the comparator was chemotherapy alone. This review considered any experimental study design including randomized controlled trials, non-randomized trials and quasi-experimental studies. The primary outcomes of interest were event-free survival, overall survival and recurrence of osteosarcoma. Secondary outcomes that were considered included health-related quality of life and any mifamurtide-related adverse events. A search for published and unpublished literature in English was undertaken (seven published literature databases, four unpublished literature databases, and three government agency and organizational websites were searched). Studies published between 1990 to June 2016 were considered. A three-step strategy was developed using MeSH terminology and keywords to ensure that all relevant studies were included related to this review. The methodological quality of included studies was assessed by two reviewers, who appraised each study independently, using a standardized Joanna Briggs Institute (JBI) critical appraisal tool. Data was extracted from the studies that were identified as meeting the criteria for methodological quality using the standard JBI data extraction tool. Due to the heterogeneity of populations and interventions in available studies, meta-analysis was not possible and results are presented in narrative form. Three papers outlining two studies involving 802 patients evaluated the effectiveness of mifamurtide in addition of chemotherapy. Results indicated no significant difference in event-free survival between the addition of mifamurtide to standard chemotherapy regimen and chemotherapy alone, both in non-metastatic and metastatic osteosarcoma patients. There was a significant difference in progression-free survival favoring the addition of mifamurtide in pulmonary metastatic and/or relapsed osteosarcoma. There was no significant difference in overall survival between the addition of mifamurtide and chemotherapy alone in metastatic osteosarcoma; however there was a significant difference favoring the addition of mifamurtide in non-metastatic osteosarcoma patients. The addition of mifamurtide resulted in a significant difference in survival after relapse in pulmonary metastatic and/or relapsed osteosarcoma patients. Both studies reported on mifamurtide-related adverse events - the first was reported as toxicity which included haematological, hepatic, renal, gastrointestinal disorders, cardiac, rhythm and nervous system disorders, ear disorders and others (infection, fever; and performance status) in metastatic osteosarcoma patients. Results were similar across all combined treatment regimens. Although no statistical analysis was undertaken, the figures suggest there were no significant differences between the treatment regimens. In the other study, mifamurtide-related adverse events were reported as clinical toxic effects of mifamurtide in relapsed osteosarcoma, which included chills, fever and headache for the initial dose of mifamurtide, while for the subsequent doses of mifamurtide all patients reported toxicity as delayed fatigue. The available evidence on the effectiveness of mifamurtide in addition to a standard chemotherapy regimen for the treatment of high-grade osteosarcoma is limited and therefore no definitive conclusions can be made.

Comparative osteohistology of Hesperornis with reference to pygoscelid penguins: the effects of climate and behaviour on avian bone microstructure.

The broad biogeographic distribution of Hesperornis fossils in Late Cretaceous Western Interior Seaway deposits has prompted questions about whether they endured polar winters or migrated between mid- and high latitudes. Here, we compare microstructures of hesperornithiform long bones from Kansas and the Arctic to investigate whether migration or Late Cretaceous polar climate affected bone growth. We also examine modern penguin bones to determine how migration and climate may influence bone growth in birds with known behaviours. Histological analysis of hesperornithiform samples reveals continuous bone deposition throughout the cortex, plus an outer circumferential layer in adults. No cyclic growth marks, zonation or differences in vasculature are apparent in the Hesperornis specimens. Comparatively, migratory Adélie and chinstrap penguin bones show no zonation or changes in microstructure, suggesting that migration is not necessarily recorded in avian bone microstructure. Non-migratory gentoos show evidence of rapid bone growth possibly associated with increased chick growth rates in high-latitude populations and large body size. The absence of histological evidence for migration in extinct Hesperornis and extant pygoscelid penguins may reflect that these birds reached skeletal maturity before migration or overwintering. This underscores the challenges of using bone microstructure to infer the effects of behaviour and climate on avian growth.

Effectiveness of mifamurtide in addition to standard chemotherapy for high-grade osteosarcoma: a systematic review protocol

Effectiveness of mifamurtide in addition to standard chemotherapy for high-grade osteosarcoma: a systematic review protocol

Avascular Necrosis of Bone after Allogeneic Hematopoietic Cell Transplantation in Children and Adolescents

We conducted a nested case-control study within a cohort of 6244 patients to assess risk factors for avascular necrosis (AVN) of bone in children and adolescents after allogeneic transplantation. Eligible patients were ≤21 years of age, received their first allogeneic transplant between 1990 and 2008 in the United States, and had survived ≥ 6 months from transplantation. Overall, 160 patients with AVN and 478 control subjects matched by year of transplant, length of follow-up and transplant center were identified. Patients and control subjects were confirmed via central review of radiology, pathology, and/or surgical procedure reports. Median time from transplant to diagnosis of AVN was 14 months. On conditional logistic regression, increasing age at transplant (≥5 years), female gender, and chronic graft-versus-host disease (GVHD) were significantly associated with increased risks of AVN. Compared with patients receiving myeloablative regimens for malignant diseases, lower risks of AVN were seen in patients with nonmalignant diseases and those who had received reduced-intensity conditioning regimens for malignant diseases. Children at high risk for AVN include those within the age group where rapid bone growth occurs as well as those who experience exposure to myeloablative conditioning regimens and immunosuppression after hematopoietic cell transplantation for the treatment of GVHD. More research is needed to determine whether screening strategies specifically for patients at high risk for developing AVN with early interventions may mitigate the morbidity associated with this complication.

Older Age, Use Of Myeloablative Regimens For Malignant Diseases and Chronic Graft-Versus-Host Disease Are Risk Factors For Avascular Necrosis Of Bone After Allogeneic Hematopoietic Cell Transplantation In Children and Adolescents

▪Avascular necrosis (AVN) of the bone is a painful and debilitating complication of allogeneic hematopoietic cell transplantation (HCT) that is associated with significant morbidity and often requires surgery. Risk factors for its development in pediatric allogeneic HCT recipients are not well described. To assess risk factors for AVN in children and adolescents following allogeneic HCT, we conducted a nested case-control study with a matched cohort of 638 patients reported to the Center of International Blood and Marrow Transplant Research who were ≤ 21 years of age, received their first allogeneic transplant between 1990 to 2008 in the United States and had survived ≥ 6 months from HCT. Overall, 160 cases with AVN were identified. Each case was matched with up to 3 controls by same year of HCT, similar length of follow-up and by transplant center (478 controls). Cases and controls were confirmed via central review of radiology, pathology and/or surgical procedure reports. The median age for cases was 15 (range 2-21) years, 49% were male, 65% had acute leukemia, 65% had received high-dose total body irradiation (TBI) based conditioning regimen, and 65% had received unrelated donor HCT. Among cases, 18% had a history of acute graft-versus-host disease (GVHD) while 56% had a history of chronic GVHD prior to development of AVN. Median time from HCT to diagnosis of AVN was 14 (range <1-172) months. We evaluated age, gender, diagnosis, conditioning regimen, TBI, donor source and GVHD as risk factors for AVN. On conditional logistic regression, increasing age at HCT, female gender and chronic GVHD were significantly associated with increased risks of AVN. Compared to patients receiving myeloablative regimens for malignant diseases, lower risks of AVN were seen in patients with non-malignant diseases and those who had received reduced intensity conditioning regimen for malignant diseases. (Table). Patients receiving unrelated donor transplant had lower risks of AVN compared to HLA-identical sibling donor HCT recipients; there was no significant interaction between donor source and GVHD status. Lack of data on pre- and post-HCT steroid exposure was a limitation of our study. Our findings suggest that children at high risk for AVN include those within the age group where rapid bone growth occurs as well as those who experience exposure to high-dose myeloablative conditioning regimens and immunosuppression post-HCT for the treatment of GVHD. Our study identifies important risk factors for AVN in a large cohort of pediatric HCT recipients. Future studies should evaluate the role of surveillance and preventive strategies for AVN in pediatric HCT recipients who are at high risk for development of AVN. Disclosures:No relevant conflicts of interest to declare.

Additive Effects of Mechanical Marrow Ablation and PTH Treatment on de Novo Bone Formation in Mature Adult Rats

Mechanical ablation of bone marrow in young rats induces rapid but transient bone growth, which can be enhanced and maintained for three weeks by the administration of parathyroid hormone (PTH). Additionally, marrow ablation, followed by PTH treatment for three months leads to increased cortical thickness. In this study, we sought to determine whether PTH enhances bone formation after marrow ablation in aged rats. Aged rats underwent unilateral femoral marrow ablation and treatment with PTH or vehicle for four weeks. Both femurs from each rat were analyzed by X-ray and pQCT, then analyzed either by microCT, histology or biomechanical testing. Marrow ablation alone induced transient bone formation of low abundance that persisted over four weeks, while marrow ablation followed by PTH induced bone formation of high abundance that also persisted over four weeks. Our data confirms that the osteo-inducive effect of marrow ablation and the additive effect of marrow ablation, followed by PTH, occurs in aged rats. Our observations open new avenues of investigations in the field of tissue regeneration. Local marrow ablation, in conjunction with an anabolic agent, might provide a new platform for rapid site-directed bone growth in areas of high bone loss, such as in the hip and wrist, which are subject to fracture.

Proteomic Technologies for the Study of Osteosarcoma

Osteosarcoma is the most common primary bone cancer of children and is established during stages of rapid bone growth. The disease is a consequence of immature osteoblast differentiation, which gives way to a rapidly synthesized incompletely mineralized and disorganized bone matrix. The mechanism of osteosarcoma tumorogenesis is poorly understood, and few proteomic studies have been used to interrogate the disease thus far. Accordingly, these studies have identified proteins that have been known to be associated with other malignancies, rather than being osteosarcoma specific. In this paper, we focus on the growing list of available state-of-the-art proteomic technologies and their specific application to the discovery of novel osteosarcoma diagnostic and therapeutic targets. The current signaling markers/pathways associated with primary and metastatic osteosarcoma that have been identified by early-stage proteomic technologies thus far are also described.