Traumatic fracture through the neurocentral synchondroses of L3 vertebra in a 5-year-old child.

Neurocentral synchondroses (NCS) are growth plates that contribute to the transverse growth of the vertebra. Fractures through these NCS are very rare and none have been reported in the lumbar spine. We present a rare case of a traumatic fracture through the neurocentral synchondroses of L3 vertebra in a 5-year-old child.

Paraphyseal changes on bone-age studies predict risk of delayed radiation-associated skeletal complications following total body irradiation.

BACKGROUND: Children undergoing total body irradiation (TBI) often develop delayed skeletal complications. Bone-age studies in these children often reveal subtle paraphyseal changes including physeal widening, metaphyseal irregularity and paraphyseal exostoses. OBJECTIVE: To investigate whether paraphyseal changes on a bone-age study following TBI indicate a predisposition toward developing other radiation-associated skeletal complications. MATERIALS AND METHODS: We retrospectively reviewed medical records and bone-age studies of 77 children receiving TBI at our institution between 1995 and 2008 who had at least 2 years of clinical follow-up and one bone-age study after TBI. We graded bone-age studies according to the severity of paraphyseal changes. All documented skeletal complications following TBI were tabulated. Kendall's tau-b was used to examine associations between degree of paraphyseal change and development of a skeletal complication. RESULTS: Kendall's tau analyses showed that physeal widening and metaphyseal irregularity/sclerosis (tau = 0.87, P < 0.001) and paraphyseal exostoses (tau = 0.68, P < 0.001) seen on bone-age studies were significantly positively associated with the development of delayed skeletal complications following TBI. Thirty percent of children with no or mild paraphyseal changes developed a delayed skeletal complication, compared with 58% of children with moderate paraphyseal changes and 90% of children with severe paraphyseal changes. CONCLUSION: Paraphyseal changes identified on a bone-age study correlate positively with the development of delayed skeletal complications elsewhere in the skeleton following TBI.

Idiopathic scoliosis, growth zones, magnetic therapy.

BACKGROUND: The study has been performed to investigate the influence of pulsed magnetic field on the bone growth plates to get new grounds of magneto therapy in AIS treatment. MATERIALS AND METHODS: Were used methods of "strong" and "weak" pulsed magnetic fields influence. RESULTS: Application of pulsed magnetic field causes an authentic inhibition of chondrocytes' active proliferation processes, decreases the index of labeled nuclei, indicating the suppression of DNA synthesis, takes place an increase in the unit weight of the more "mature" differentiated chondrocytes. The final result of these effects is the accelerated synostosis of bones' growth plates. CONCLUSION: Regardless of the reasons that cause growth infringements, the operating organ in the chain is the body's growth plate. Therefore, the appliance of magnetic fields in AIS treatment can be considered as a perspective one concerning growth plates' functional activity local management. To our point of view, the potential of magneto therapy methods in child's orthopedic treatment is significantly higher compared with modern practice.

Growth Modulation by Stimulating the Growth Plate: A Pilot Study.

This study investigates the ability of low-intensity pulsed ultrasound (LIPUS) or direct injection of recombinant growth hormone (rGH) to stimulate local growth of long bones. In a randomized controlled animal trial, healthy immature rabbits were allocated to 1 of the following 4 conditions: epiphyseal rGH periosteal injection, transdermal LIPUS, saline periosteal injection, or no treatment. New bone deposition was labeled with calcein at days 1 and 18, and microscopic measurements of growth were conducted by blinded observers. Statistically significant differences in growth were observed between the LIPUS and rGH stimulated legs compared with contralateral control legs (35% p = 0.04 and 41% p = 0.04, respectively); whereas no difference was observed between the 4 control groups (p = 0.37). There was no evidence of physeal bar formation, suggesting that direct injection of rGH and application of LIPUS around the distal femoral physis in rabbits may have a positive effect on microscopic growth without short-term adverse sequelae.

Microarray analysis of irradiated growth plate zones following laser microdissection shows later importance of differentially expressed genes during radiorecovery.

PURPOSE: Potential targets for selective radiorecovery modulation were investigated via the identification of late upregulated genes and pathways during growth plate chondrocyte recovery. METHODS AND MATERIALS: Three groups of six 5-week-old male Sprague-Dawley rats underwent fractionated irradiation to the right tibiae over 5 days totaling 17.5 Gy and were then killed at 7, 11, and 16 days following the first radiotherapy fraction. The growth plates were collected from the proximal tibiae bilaterally and subsequently underwent laser microdissection to separate reserve, perichondral, proliferative, and hypertrophic zones. Differential gene expression was analyzed between irradiated right and nonirradiated left tibiae using RAE230 2.0 GeneChip microarray, compared between zones and time points, and subjected to functional pathway cluster analysis with real-time polymerase chain reaction (PCR) to confirm selected results. RESULTS: The reserve zone showed the greatest number of differentially expressed genes and enriched pathways: 259 and 134, respectively. Differentially expressed genes included: Timp3, Gpx1, Gas6, Notch2, VEGF, and HIF-1. Enriched pathways included the developmental processes of regeneration, antiapoptosis, developmental growth, tissue regeneration, mesenchymal cell proliferation, negative regulation of immune response, and determination of symmetry. The reserve zone late upregulation of genes was validated using real-time PCR for Mgp, Gas6, and Eef1a1. CONCLUSIONS: A significant difference in late upregulated genes between growth plate zones exists. The reserve zone shows the greatest change, containing a 10-fold increase in the total number of genes differentially expressed between days 7 and 16. These findings suggest that reserve zone chondrocytes may play a later role in growth plate recovery response following irradiation.

[Effect of the impulse magnetic field on the growth bone plates in experimental animals].

The influence of impulse magnetic field (1.5 T) on growth bone plates of the rabbit has been studied. It has been found that this field produces the inhibitory action on the functional activity of growth bone plates.

Response to GH Treatment After Radiation Therapy Depends on Location of Irradiation.

OBJECTIVES: Cancer survivors with GH deficiency (GHD) receive GH therapy (GHT) after 1+ year observation to ensure stable tumor status/resolution. HYPOTHESIS: Radiation therapy (RT) to brain, spine, or extremities alters growth response to GHT. AIM: Identify differences in growth response to GHT according to type/location of RT. METHODS: The Pfizer International Growth Database was searched for cancer survivors on GHT for ≥5 years. Patient data, grouped by tumor type, were analyzed for therapy (surgery, chemotherapy, RT of the focal central nervous system, cranial, craniospinal, or total body irradiation [TBI] as part of bone marrow transplantation), sex, peak stimulated GH, age at GHT start, and duration from RT to GHT start. Kruskal-Wallis test and quantile regression modeling were performed. RESULTS: Of 1149 GHD survivors on GHT for ≥5 years (male 733; median age 8.4 years; GH peak 2.8 ng/mL), 431 had craniopharyngioma (251, cranial RT), 224 medulloblastoma (craniospinal RT), 134 leukemia (72 TBI), and 360 other tumors. Median age differed by tumor group (P < 0.001). Five-year delta height SD score (SDS) (5-year ∆HtSDS; median [10th-90th percentile]) was greatest for craniopharyngioma, 1.6 (0.3-3.0); for medulloblastoma, 5-year ∆HtSDS 0.9 (0.0-1.9); for leukemia 5-year ∆HtSDS, after TBI (0.3, 0-0.7) versus without RT (0.5, 0-0.9), direct comparison P < 0.001. Adverse events included 40 treatment-related, but none unexpected. CONCLUSIONS: TBI for leukemia had significant impact on growth response to GHT. Medulloblastoma survivors had intermediate GHT response, whereas craniopharyngioma cranial RT did not alter GHT response. Both craniospinal and epiphyseal irradiation negatively affect growth response to GH therapy compared with only cranial RT or no RT.

Histomorphometric evidence of growth plate recovery potential after fractionated radiotherapy: an in vivo model.

This study evaluated the hypothesis that early growth plate radiorecovery is evident by growth rate, histomorphometric and immunohistochemical end points after exposure to clinically relevant fractionated radiation in vivo. Twenty-four weanling 5-week-old male Sprague-Dawley rats were randomized into eight groups. In each animal, the right distal femur and proximal tibia were exposed to five daily fractions of 3.5 Gy (17.5 Gy) with the left leg serving as a control. Rats were killed humanely at 7, 8, 9, 10, 11, 14, 15 and 16 days after the first day of radiation exposure. Quantitative end points calculated included individual zonal and overall growth plate heights, area matrix fraction, OTC-labeled growth rate, chondrocyte clone volume and numeric density, and BrdU immunohistochemical labeling for proliferative index. Transient postirradiation reductions occurred early and improved during observation for growth rate, proliferative indices, transitional/hypertrophic zone matrix area fraction, proliferative height, and clonal volume. Reserve and hypertrophic zone height remained increased during the period of observation. The current model, using a more clinically relevant fractionation scheme than used previously, shows early evidence of growth plate recovery and provides a model that can be used to correlate temporal changes in RNA and protein expression during the early period of growth plate recovery.

Effects of increasing doses of samarium-153-ethylenediaminetetramethylene phosphonate on axial and appendicular skeletal growth in juvenile rabbits.

INTRODUCTION: Targeted radiotherapy using samarium-153-ethylenediaminetetramethylene phosphonate (153 Sm-EDTMP) is currently under investigation for treatment of osteosarcoma. Osteosarcoma often occurs in children, and previous studies on a juvenile rabbit model demonstrated that clinically significant damage to developing physeal cartilage may occur as a result of systemic 153 Sm-EDTMP therapy. The aim of this study was to evaluate the late effects of 153 Sm-EDTMP on skeletal structures during growth to maturity and to determine if there is a dose response of 153 Sm-EDTMP on growth of long bones. METHODS: Female 8-week-old New Zealand white rabbits were divided into three treatment groups plus controls. Each rabbit was intravenously administered a predetermined dose of 153 Sm-EDTMP. Multiple bones of each rabbit were radiographed every 2 months until physeal closure, with subsequent measurements made to assess for abbreviated bone growth. Statistical analyses were performed to determine the differences in bone length between groups, with significance set at P<.05. RESULTS: Significant differences in lengths of multiple bones were detected between the high-dose group and other treatment groups and controls at each time interval. A significant difference in lengths of the tibias was also noted in the medium-treatment group, compared to controls. Mean reduction of bone length was first detected at 4 months and did not increase significantly over time. CONCLUSIONS: These data suggest that clinically significant bone shortening may occur as a result of high-dosage administration of 153 Sm-EDTMP. Further investigation regarding the effects of bone-seeking radiopharmaceuticals on bone growth and physeal cartilage is warranted.

Comparison of the protective effects of melatonin and amifostine on radiation-induced epiphyseal injury.

PURPOSE: We compared the effects of amifostine and melatonin in preventing radiation-induced epiphyseal growth plate injury in rats. MATERIALS AND METHODS: Four-week-old (65-85 g), growing male Sprague-Dawley rats were randomly assigned to receive radiation alone, at 25 Gy in three fractions (group R), or this dose of fractionated radiation proceeded by prophylactic amifostine 200 mg/kg i.p. (group A), melatonin 15 mg/kg i.p. (group M), or amifostine + melatonin (group AM). The right rear extremity of each animal was irradiated while the contralateral leg was shielded from radiation, as a control. Bone growth based on the length of the tibia, femur, and overall limb was calculated 6 weeks after the treatment. RESULTS: In groups R, A, M, and AM, the mean growth loss (GL) for the overall limb was 56.9 +/- 8.1%, 46.8 +/- 7.7%, 36.6 +/- 4.3%, and 38.5 +/- 5.1%, respectively. The limb length discrepancies (LLD) in groups R, A, M, and AM were 13.8 +/- 1.4%, 10.5 +/- 0.3%, 7.4 +/- 0.7%, and 8.8 +/- 1.1%, respectively. Differences in LLD were significant between each treatment group and group R (range: p = 0.0001-0.001). Differences in either of mean GL and LLD were not significant between groups M and AM; however both of these groups had significantly less GL and LLD than group A. CONCLUSIONS: We observed a superior radioprotective function of melatonin over amifostine in preventing radiation-induced epiphyseal growth plate injury, without any increase in radioprotective effect by adding amifostine to melatonin.

Connective tissue growth factor and insulin-like growth factor 2 show upregulation in early growth plate radiorecovery response following irradiation.

INTRODUCTION: The growth plate response following radiotherapy is poorly understood. In particular, little is known about the changes in growth plate growth factors and cytokines following irradiation. The hypothesis was that a limited number of growth factors and cytokines play a role in growth plate proliferative and hypertrophic chondrocyte radio-recovery. METHODS: The right limbs of 6 rats were irradiated (17.5 Gy), leaving the left limbs as controls. Limbs were harvested 1 (n = 3) and 2 (n = 3) weeks later. Microarrays were constructed from chondrocytes obtained by laser microdissection from the proliferative zone (PZ) and the hypertrophic zone (HZ) of normal and irradiated tibia growth plates. Real-time PCR was used to confirm the expression of parathyroid hormone receptor 1 (Pthr1), connective tissue growth factor (CTGF), insulin-like growth factor I receptor (IGF1R), insulin-like growth factor II (IGF2), interleukin 17beta (IL17b) and chemokine ligand 12 (CXCL12). RESULTS AND CONCLUSIONS: IGF2 is upregulated in the PZ and CTGF is upregulated in both the PZ and HZ 1 week after irradiation, prior to the histomorphometric appearance of growth plate recovery in this immature animal radiation model, supporting their role in stimulating early return of the growth plate. By 2 weeks after irradiation, a number of growth factors and cytokines, including CTGF and Pthr1 in both zones, CXCL12 and its receptor in the PZ, and IL17b and bone morphogenetic protein 2 in the HZ, show upregulation, suggesting a possible later role in radiorecovery. The effects of irradiation on Pthr1, CTGF, IGF2 and CXCL12 in PZ and Pthr1, CTGF, IL17b and IGF1R in the HZ determined by microarray and real-time RT-PCR was highly correlated (r = 0.797, p < 0.05 in the PZ and r = 0.875, p < 0.01 in the HZ, respectively).

Combination radioprotectors maintain proliferation better than single agents by decreasing early parathyroid hormone-related protein changes after growth plate irradiation.

Our hypothesis was that combinations of radioprotectors would be more effective than individual agents in minimizing the effects of radiation on the growth plate after single-fraction hind-limb irradiation of Sprague-Dawley rats. At 2 days postirradiation, the decrease in parathyroid hormone-related protein and parathyroid hormone receptor 1 expression in the irradiated growth plate transitional and hypertrophic zones was reversed in both of the combination groups but persisted in the groups treated with the individual drugs. By 2 weeks, positive findings unique to the combination-treatment animals included greater mean proliferation in the irradiated growth plate than on the contralateral side, smaller limb length discrepancies, reversal of the increased overall matrix area fraction, and reversal of the usual deficiency in Indian hedgehog staining in the irradiated hypertrophic zone. While all treatments had a positive effect in reversing the decrease in B-cell leukemia 2 protein and coincident increase in Bax previously observed 2 weeks postirradiation, the two combination groups had a more robust effect. Combinations of radioprotectors may achieve their beneficial additive effects in the growth plate by decreasing the usual early drop in parathyroid hormone-related protein and parathyroid hormone receptor 1 after irradiation, resulting in a cascade of parathyroid hormone-related protein-mediated events.

Restoration of growth plate function following radiotherapy is driven by increased proliferative and synthetic activity of expansions of chondrocytic clones.

Radiation therapy encompassing an active epiphysis can negatively impact the potential for bone growth by disrupting cell-cycle progression and accelerating apoptosis and terminal differentiation in physeal chondrocytes. Despite functional derangement following radiation exposure, the irradiated growth plate retains a capacity for regeneration and recovery of growth. The purpose of this study was to characterize the initial sequence of events leading to functional growth recovery in irradiated weanling rat growth plates. We hypothesized that growth in an irradiated epiphysis would be partially restored due to the expansion of chondrocytic clones. Stereological histomorphometry was used to compare chondrocytic cell and matrix turnover between the first and second week following irradiation, and to determine the relative contribution of each of the cellular and extracellular matrix (ECM) compartments to growth. We found that restoration of growth in the irradiated limb was strongly associated with the proliferative activity and production of ECM by these chondrocytic clones, as they expand in average volume, but not in numerical density. We conclude that chondrocytes forming expansive clones and exhibiting increased mitotic and matrix synthesis activity initiate the early restoration of function in the irradiated growth plate, and would be a logical target for strategies to restore full growth potential.

Effects of electromagnetic field (1.8/0.9 GHz) exposure on growth plate in growing rats.

The purpose of this study was to determine the effects of whole-body electromagnetic field (EMF) exposure on growth plates in growing male rats. Two groups of rats were exposed to either 900 MHz EMF or 1800 MHz EMF 2 h/day for 90 days. Sham control rats were kept under similar conditions without exposure to the EMF. The rats in the EMF group experienced a more rapid weight gain and increase in length (p < 0.05). Calcium, growth hormone, estradiol and testosterone levels in the EMF groups were higher (p < 0.05). The Safranin O staining density of femoral growth plate was lowest in the reserve zone of rats exposed to 1800 MHz and was increased in the proliferative zone of the control group (p < 0.05). The trabecular zone was thinnest among all zones and the reserve and proliferative zones were thicker (p < 0.05) than other zones in 1800 MHz group.In conclusion, 1800 MHz and 900 MHz EMF may cause prolong the growth phase in growing rats.

The effects of ionizing radiation on the growth plate in rat tibiae.

The deleterious effects of ionizing radiation on the growth plate continue to be cause for concern. This study evaluated the ionizing radiation effects on bone development and growth plate in the tibia of rats. All animals were submitted to ionizing radiation on the left leg. The animals were divided into two groups and euthanized 30 and 60 days after radiation. The tibiae were removed and separated into groups: control 30 days, irradiated 30 days, control 60 days and irradiated 60 days. Animals in each group (n = 7) were used for macroscopic and histological analysis. The irradiated tibiae showed arrested growth, angular deformity and limb length discrepancy when compared with nonirradiated tibiae. There was statistical difference between control and radiation groups in all the parameters analyzed, except in the lateral-medial thickness of the distal epiphysis. Histological analysis showed evident changes in the growth plate, which was thicker in the Groups irradiated for 30 days, and irradiated for 60 days, compared with their respective controls. The growth plate showed wide areas with disorganized zones of chondrocytes and severely reduced calcification zone. It was concluded that ionizing radiation damaged the growth plate, compromised the endochondral ossification process, and resulted in complete arrest of bone development.

Side Effects of Radiation in Bone and Cartilage: An FT-IR Analysis.

Although radiation therapy is an essential treatment of cancers, it is associated with unwanted complications. The purpose of this review is to summarize the current knowledge regarding the side effects of radiation in bone and articular cartilage and to recommend Fourier transform infrared spectroscopy to monitor the differences in infrared spectra between healthy and irradiated bone and cartilage.

Effects of X-ray irradiation on terminal differentiation and cartilage matrix calcification of rabbit growth plate chondrocytes in culture.

The retardation of long bone growth caused by irradiation is thought to be closely related to the impairment of growth plate function, but its mechanism remains unclear. In this study, we examined the effects of irradiation on the terminal differentiation of growth plate chondrocytes and on calcification. Chondrocytes were isolated from the growth plate of the ribs of four-week-old rabbits and inoculated at a high density on a type-I collagen-coated dish. Following logarithmic proliferation, they reached confluence (premature chondrocytes), then matured (mature chondrocytes), and became hypertrophied (hypertrophic chondrocytes). 10 Gy or less irradiation of the premature chondrocytes potently inhibited the terminal differentiation and matrix mineralization. Irradiation inhibited chondrocyte hypertrophy and suppressed alkaline phosphatase induction and the expression of type-X collagen without changing the protein composition profile of any other cell layer. Premature cells had the highest radiosensitivity. The sensitivity was decreased as the cells differentiated; the effects of irradiation on hypertrophic chondrocytes with terminal differentiation-related phenotypes were reduced. This study showed that 10 Gy or less irradiation of growth plate chondrocytes impaired terminal differentiation and mineralization. Since chondroclasts and bone marrow cells invade only to the mineralized cartilage, the induction of calcification in cartilage matrices is one of the most important steps in endochondral ossification. Therefore, it is conceivable that the damage in the growth plate induced by irradiation could account for the subsequent abnormal bone and skeletal growth.

Radiation fractionation sensitivity of epiphyseal cartilage in a weanling rat model.

Tibial growth at 100 days of age was measured in Sprague-Dawley rats treated at 21 days to the proximal tibia with various courses of fractionated radiation. In split-dose and multiple-fraction experiments, a minimum interval of 5-6 hr was required to achieve maximal sparing of growth arrest. Total doses required to reduce growth to 80% of untreated controls were computed from dose-response curves for fractionated radiation (dose/fraction 1.0-10 Gy). When fitted to a linear-quadratic model of radiation response the data described an estimated alpha/beta of 4.47 (95% C.I. (3.71, 5.23) Gy). This value suggests that the fractionation sensitivity of the epiphyseal plate is substantially greater than that of most neoplasms, predicting a favorable therapeutic gain with the use of hyperfractionated radiation therapy.

Response of growing bone to irradiation: a proposed late effects scoring system.

The effect of radiation on epiphyseal bone growth is one of the most important dose-limiting factors in the radiotherapeutic management of children with malignant neoplasms. Clinical and laboratory evidence suggest that many factors may influence the severity of radiation-induced growth arrest. However, the absence of a consistent scoring system for late effects has hampered efforts to analyze the influence of various therapeutic maneuvers or to compare and collate results from different reported series. In this review, laboratory and clinical studies of radiation effects on growing bone are summarized, and a late effects scoring system is proposed.

Temporal changes in PTHrP, Bcl-2, Bax, caspase, TGF-beta, and FGF-2 expression following growth plate irradiation with or without radioprotectant.

This study examined temporal changes in growth plate apoptosis molecules and growth factors in an animal model of radiation injury with and without a radioprotectant. Thirty weanling 5-week Sprague-Dawley rats underwent right knee irradiation with single-fraction 17.5 Gy while the left served as internal control. Six animals each were sacrificed at 0.5, 1, 2, 3, or 4 weeks after irradiation. Half of the animals received pretreatment with amifostine (WR-2721) radioprotectant. Immunohistochemical staining for PTHrP, Bcl-2, Bax, caspase-3, FGF-2, and TGF-beta was performed. PTHrP decreased to a nadir at 1 week after irradiation but rebounded to above control levels at 2 weeks in the reserve and transitional zones. The radioprotectant amifostine blunted the decrease in PTHrP but kept PTHrP expression lower than controls during the rebound phase in untreated irradiated animals. Hypertrophic zone Bax expression was decreased by amifostine in both irradiated and non-irradiated limbs at 1 and 2 weeks. FGF, TGF-beta, Bcl-2, and caspase levels generally decreased at 1 week and returned thereafter toward control levels. These findings underscore the importance of PTHrP in response to growth plate irradiation and show the novel finding of a decrease in Bax expression with amifostine pretreatment.