Estrogen receptors in breast and bone: from virtue of remodeling to vileness of metastasis.

Bone metastasis is a prominent cause of morbidity and mortality in cancer. High rates of bone colonization in breast cancer, especially in the subtype expressing estrogen receptors (ERs), suggest tissue-specific proclivities for metastatic tumor formation. The mechanisms behind this subtype-specific organ-tropism remains largely elusive. Interestingly, as the major driver of ER+ breast cancer, ERs also have important roles in bone development and homeostasis. Thus, any agents targeting ER will also inevitably affect the microenvironment, which involves the osteoblasts and osteoclasts. Yet, how such microenvironmental effects are integrated with direct therapeutic responses of cancer cells remain poorly understood. Recent findings on ER mutations, especially their enrichment in bone metastasis, raised even more provocative questions on the role of ER in cancer-bone interaction. In this review, we evaluate the importance of ERs in bone metastasis and discuss new avenues of investigation for bone metastasis treatment based on current knowledge.

The sacroiliac spine - computer simulation of motion and modeling of the ligaments.

Using an interactive, 3D, kinematic simulation of the human skeleton, the motion of the sacro-iliac (SI) joint is modeled based upon descriptions available in the literature. The major ligaments are added to the simulation data structure using deformable cubic B-spline curve paths. Ligament strains were generated and studied in response to the motion simulations. Results improve our understanding of sacro-iliac kinematics and highlight the importance of further studies to elucidate pathological as well as normal SI joint and ligament function.

The effect of retained intramedullary nails on tibial bone mineral density.

BACKGROUND: Intramedullary nailing has become a standard treatment for adult tibial shaft fractures. Retained intramedullary nails have been associated with stress shielding, although their long-term effect on decreasing tibial bone mineral density is currently unclear. The purpose of this study was to determine if retained tibial intramedullary nails decrease tibial mineral density in patients with successfully treated fractures. METHODS: Patients treated with statically locked intramedullary nails for isolated, unilateral tibia shaft fractures were studied. Inclusion required that fracture had healed radiographically and that the patient returned to the pre-injury activity level. Data on patient demographic, fracture type, surgical technique, implant, and post-operative functional status were tabulated. Dual energy X-ray absorptiometry was used to measure bone mineral density in selected regions of the affected tibia and the contralateral intact tibia. Image reconstruction software was employed to ensure symmetry of the studied regions. FINDINGS: Twenty patients (mean age 43; range 22-77 years) were studied at a mean of 29 months (range 5-60 months) following intramedullary nailing. There was statistically significant reduction of mean bone mineral density in tibiae with retained intramedullary nails (1.02 g/cm(2) versus 1.06 g/cm(2); P=0.04). A significantly greater decrease in bone mineral density was detected in the reamed versus non-reamed tibiae (-7% versus +6%, respectively; P<0.05). INTERPRETATION: The present study demonstrates a small, but statistically significant overall bone mineral density decrease in healed tibiae with retained nails. Intramedullary reaming appears to be a factor potentiating the reduction of tibia bone mineral density in long-term nail retention.

Osteoinduction by ex vivo adenovirus-mediated BMP2 delivery is independent of cell type.

The objective of the study was to analyze and compare the abilities of various human cell types with inherently dissimilar osteogenic potentials to induce heterotopic bone formation following ex vivo transduction with two distinct adenoviral vectors encoding bone morphogenetic protein type 2 (BMP2). The cells comprised primary human bone marrow mesenchymal stem cells (BM-MSCs), primary human skin fibroblasts (SFs), and a human diploid fetal lung cell line (MRC-5). The vectors included adenovirus type 5 or a chimeric adenovirus type 5 with the fiber gene of adenovirus type 35 (Ad5F35-BMP2), both demonstrating significantly different expression of BMP2 in vitro. The experimental groups consisted of the three human cell types transduced with each of the two adenoviral vectors. Using nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice, the transduced cells were injected intramuscularly following ex vivo adenoviral transduction. The nature and extent of heterotopic bone formation were analyzed radiographically and histologically. At 14 days postinjection, abundant, highly mineralized bone was formed in mice injected with Ad5F35-BMP2-transduced cells irrespective of the cell type. There was no statistically significant difference in the amount of bone formed between BM-MSCs, SFs, and MRC-5 cells transduced with Ad5F35-BMP2, as assessed from bone surface area on biplanar plain radiography. Substantially lesser amounts or no bone could be detected in mice injected with cells transduced with Ad5-BMP2. Immunohistochemical analysis confirmed the presence of human cells in muscle as early as 2 days postdelivery; however, at 6-7 days after injection, the transduced cells could not be detected in surrounding muscle, or in the heterotopic bone, indicating the host origin of the newly formed bone. The results of the study demonstrate no significant difference in osteoinductive properties between BM-MSCs, SFs, and MRC-5 cells transduced ex vivo with the same type of adenovirus encoding BMP2. The level of BMP2 expression appears to be a crucial factor determining the extent of heterotopic bone formation and was significantly affected by the type of adenovirus used. In the cell types studied, Ad5F35-BMP2 was more efficacious than Ad5-BMP2 in providing adequate levels of BMP2 for efficient osteoinduction.

Adenovirus-mediated BMP2 expression in human bone marrow stromal cells.

Recombinant adenoviral vectors have been shown to be potential new tools for a variety of musculoskeletal defects. Much emphasis in the field of orthopedic research has been placed on developing systems for the production of bone. This study aims to determine the necessary conditions for sustained production of high levels of active bone morphogenetic protein 2 (BMP2) using a recombinant adenovirus type 5 (Ad5BMP2) capable of eliciting BMP2 synthesis upon infection and to evaluate the consequences for osteoprogenitor cells. The results indicate that high levels (144 ng/ml) of BMP2 can be produced in non-osteoprogenitor cells (A549 cell line) by this method and the resultant protein appears to be three times more biologically active than the recombinant protein. Surprisingly, similar levels of BMP2 expression could not be achieved after transduction with Ad5BMP2 of either human bone marrow stromal cells or the mouse bone marrow stromal cell line W20-17. However, human bone marrow stromal cells cultured with 1 microM dexamethasone for four days, or further stimulated to become osteoblast-like cells with 50 microg/ml ascorbic acid, produced high levels of BMP2 upon Ad5BMP2 infection as compared to the undifferentiated cells. The increased production of BMP2 in adenovirus transduced cells following exposure to 1 microM dexamethasone was reduced if the cells were not given 50 microg/ml ascorbic acid. When bone marrow stromal cells were allowed to become confluent in culture prior to differentiation, BMP2 production in response to Ad5BMP2 infection was lost entirely. Furthermore, the increase in BMP2 synthesis seen during differentiation was greatly decreased when Ad5BMP2 was administered prior to dexamethasone treatment. In short, the efficiency of adenovirus mediated expression of BMP2 in bone marrow stromal cells appears to be dependent on the differentiation state of these cells.

Tibial intramedullary nail distal interlocking screw placement: comparison of the free-hand versus distally-based targeting device techniques.

Intramedullary nailing is the standard treatment for closed and some open unstable diaphyseal tibia fractures. Fluoroscopy, while essential for proper nail placement can subject the surgical team and patient to substantial radiation. A new targeting system for tibia nail distal interlocking was developed by Orthofix to limit fluoroscopy. This prospective clinical study compares the Orthofix targeting system versus a free-hand technique for the tibial nail distal interlocking. Fifty eight consecutive patients with sixty tibial fractures amenable for nail fixation were randomly assigned into two equal groups: Group 1: Orthofix distally based distal targeting device and Group 2: a free-hand technique. In all the cases stabilization was achieved with a reamed statically locked tibial nail. Recorded data included accuracy of screw placement, duration of surgery prior to and during distal interlocking, and the fluoroscopy time prior to and during distal interlocking. Both groups revealed comparable fracture patterns. In all fractures the technical aspects of the surgical treatment were performed without complications. There was no statistically significant difference between the groups in the mean time of surgery prior to (62.02 vs. 61.01 min, P=0.92) and during distal interlocking (17.06 vs. 19.08 min, P=0.55), or in the total surgical time (81 vs. 85 min), respectively. Neither was there a statistically significant difference in the mean fluoroscopy time prior to distal interlocking (69 vs. 81 s, p=0.22) nor in the total fluoroscopy time (84 vs. 117 s). There was however, a statistically significant difference between the Orthofix and free-hand groups with regards to the mean fluoroscopy time during distal interlocking (15 vs. 36 s, P=0.01, respectively). This study demonstrates that the distally based distal targeting device by Orthofix for tibial nailing can significantly decrease the mean fluoroscopy time necessary to complete distal interlocking versus free-hand technique.

Bending of the Cotrel-Dubousset instrumentation after direct trauma: a case report.

STUDY DESIGN: Case report. OBJECTIVES: To describe a fracture through the fusion mass of a spine that had been corrected previously with Cotrel-Dubousset rods. These rods had failed in bending after direct trauma. SUMMARY OF BACKGROUND DATA: Nine years after successful treatment of scoliosis with Cotrel-Dubousset instrumentation, the patient was in a motor vehicle accident and sustained a hyperextension spine injury with complete L1-L2 paraplegia and disruption of the fusion mass. The Cotrel-Dubousset instrumentation rods, which failed in bending, could not be corrected in situ, and the angulated segments had to be resected. The spine then became extremely unstable, and the patient consulted the authors for definitive stabilization. RESULTS: The spine was stabilized by attaching the proximal and distal retained Cotrel-Dubousset instrumentation to supplemental rods in a "domino" fashion. Crosslinks were added to improve the torsional stability. Intraoperatively, the fracture was well reduced, and the fixation was stable. A posterolateral fusion was performed with allogenic bone graft. CONCLUSION: Bent Cotrel-Dubousset instrumentation rods are still very strong and may not correct in situ.- If resection is required, the retained portions of Cotrel-Dubousset instrumentation can serve as attachments to restore stable fixation a "domino"technique.

The cylindrical titanium mesh cage for treatment of a long bone segmental defect: description of a new technique and report of two cases.

This report describes a new technique for treatment of a segmental defect in long bones that uses a cylindrical titanium mesh cage, in combination with cancellous bone allograft and demineralized bone matrix putty (Grafton), stabilized with a statically locked intramedullary nail. Two clinical cases of tibia defects treated with this technique are presented. At the one-year follow-up, radiographically both cases demonstrated excellent limb alignment, stability, and bony healing. Immediate full weight-bearing was initiated in each case, and early limb functional recovery was achieved. Preliminary data suggest that this technique may be a reasonable alternative to currently used methods for management of select long bone segmental defects.

In vitro growth and activity of primary chondrocytes on a resorbable polylactide three-dimensional scaffold.

Sheep articular chondrocytes were cultured for 3, 6, and 9 weeks on a three-dimensional porous scaffold from poly(L/DL-lactide) 80/20%. Cell growth and activity was estimated from the amount of proteoglycans attached to the polylactide scaffold and the amounts of DNA and proteins measured in the cell lysate. Cell morphology was assessed from scanning electron microscopy. Histochemical staining of proteoglycans present in the sponge was used to visualize the chondrocyte ingrowth in the scaffold. The amounts of DNA, proteins, and proteoglycans increased with time of culturing. Chondrocytes on the polylactide scaffold maintained their round shape. The cell ingrowth into the sponge progressed with time of culturing and proceeded from the upper surface of the sponge toward its lower surface. At 9 weeks, the chondrocytes filled the whole scaffold and reached the opposite side of the sponge. The proteoglycans network was, however, more dense at the upper half of the scaffold.

Regeneration of segmental diaphyseal defects in sheep tibiae using resorbable polymeric membranes: a preliminary study.

OBJECTIVE: To investigate whether a long bone cortex of well-defined thickness can be regenerated by using an anatomically designed membranous resorbable "tube-in-tube" implant and to establish the functions of membranes in the healing of segmental diaphyseal bone defects larger than the "critical size." DESIGN: Bone healing in segmental diaphyseal defects larger than the critical size in the sheep tibiae covered with a single porous tubular membrane or implanted with anatomically shaped porous double tube-in-tube membranes was evaluated. Membranes with different pore structures were applied alone and/or in combination with autogenous bone graft. BACKGROUND: Healing of segmental diaphyseal bone defects in animals can be enhanced by covering the defects with resorbable polylactide membranes. Based on the results of bone healing in defects ten millimeters long in the rabbit radii, it was suggested that the membrane prevents muscle and soft tissue from invading the defect and maintains osteogenic cells and osteogenic substances within the space covered with membrane, thus promoting new bone formation. The functions of membranes may differ, however, depending on the size and the location of the defect and on the experimental species used. Bone defects larger than the critical size may not heal at all, even if membranes are used. The critical-size defect is defined as the smallest bone defect that does not heal spontaneously when covered with polymeric membranes. To heal such defects, it is mandatory that membranes are used in combination with autogenic bone graft and/or a suitable bone substitute. If bone graft is used to fill the defect, the structure and geometry of the covering membrane will determine whether the graft will be vascularized and/or nourished from the surrounding soft tissue and, in consequence, survive. It can be appreciated that bone healing in areas of good vascularity should be more efficient than bone healing in poorly vascularized areas. The influence of all these factors on healing of bone in segmental diaphyseal defects covered with membranes is not known. METHODS: Four-centimeter-long diaphyseal segmental defects in the tibiae of six- to seven-year-old Swiss mountain sheep were covered with resorbable membranes from poly(LDL-lactide). In Group 1, a single microporous external membrane was used. In Group 2, one microporous membrane was inserted into the medullary cavity at the cut ends of the tibiae (internal membrane), and the other microporous membrane was placed on the outer surface of the cortex (external membrane). In Group 3, a single microporous external membrane was also laser-perforated to produce openings with a diameter in the range of 800 to 900 micrometers. In Group 4, the defect was filled with autogenous cancellous bone graft and covered with a single perforated membrane. In Group 5, one perforated internal membrane was inserted into the medullary cavity at the cut ends of the tibiae, and the other perforated membrane was placed on the outer surface of the cortex. Group 6 was identical to Group 5, except that cancellous bone graft was placed in the space between these two membranes. RESULTS: There was no bone healing in Groups 1, 2, 3, and 5. Only in Groups 4 and 6 did the defects heal. In Group 4, new bone was dispersed across the "medullary canal" formed by the membrane. In Group 6, the new bone had grown into the space between the outer and inner membranes, forming the "neocortex." CONCLUSIONS: The resorbable polymeric implant consisting of two concentric perforated membranes (the tube-in-tube implant) used in combination with cancellous bone graft to treat segmental diaphyseal defects in sheep tibiae allows for the reconstitution of the "neocortex" with well-defined thickness. (ABSTRACT TRUNCATED)