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Thomas A Einhorn

Publications and source records attributed to Thomas A Einhorn.

At least 19 recordsLinked to original sources
PubMed2006

Fracture healing in the elderly patient.

Clinical experience gives rise to the impression that there are differences in fracture healing in different age groups. It is evident that fractures heal more efficiently in children than in adults. However, minimal objective knowledge exists to evaluate this assumption. Temporal, spatial, and cellular quantitative and qualitative interrelationships, as well as signaling molecules and extracellular matrix have not been comprehensively and adequately elucidated for fracture healing in the geriatric skeleton. The biological basis of fracture healing will provide a context for revealing the pathophysiology of delayed or even impaired bone regeneration in the elderly. We will summarize experimental studies on age-related changes at the cellular and molecular level that will add to the pathophysiological understanding of the compromised bone regeneration capacity believed to exist in the elderly patient. We will suggest why this understanding would be useful for therapeutics focused on bone regeneration, in particular fracture healing at an advanced age.

Aged↗
PubMed2006

Three-dimensional reconstruction of fracture callus morphogenesis.

Rat and mouse femur and tibia fracture calluses were collected over various time increments of healing. Serial sections were produced at spatial segments across the fracture callus. Standard histological methods and in situ hybridization to col1a1 and col2a1 mRNAs were used to define areas of cartilage and bone formation as well as tissue areas undergoing remodeling. Computer-assisted reconstructions of histological sections were used to generate three-dimensional images of the spatial morphogenesis of the fracture calluses. Endochondral bone formation occurred in an asymmetrical manner in both the femur and tibia, with cartilage tissues seen primarily proximal or distal to the fractures in the respective calluses of these bones. Remodeling of the calcified cartilage proceeded from the edges of the callus inward toward the fracture producing an inner-supporting trabecular structure over which a thin outer cortical shell forms. These data suggest that the specific developmental mechanisms that control the asymmetrical pattern of endochondral bone formation in fracture healing recapitulated the original asymmetry of development of a given bone because femur and tibia grow predominantly from their respective distal and proximal physis. These data further show that remodeling of the calcified cartilage produces a trabecular bone structure unique to fracture healing that provides the rapid regain in weight-bearing capacity to the injured bone.

Animals↗
PubMed2006

Analysis of fracture healing by large-scale transcriptional profile identified temporal relationships between metalloproteinase and ADAMTS mRNA expression.

The aim of this study was to validate the use of transcriptional profiling as a means of characterizing the complex interactions of the thousands of genes that are expressed during fracture healing. Standard mid-diaphyseal tibia fractures were generated in C57/B6 murine tibiae and the transcriptional expression of approximately 13,000 genes was assessed. Three time points after fracture were assessed: day 3, representative of the inflammatory phase; day 10, representative of the peak of cartilage formation; and day 21, representative of the period of primary bone formation and coupled remodeling. A self-organizing mapping approach of the data revealed the temporal relationships between the expression of mRNAs for extracellular matrix proteins and the proteases that degrade the proteoglycan and collagenous matrices. A broad group of extracellular matrix protein mRNAs representative of basement membranes, blood vessels and cartilage all showed elevated expression over the first 21 days of fracture healing. The sorting of the data identified an orderly temporal expression of the metalloproteinases and ADAMTS during the progression of fracture healing with (MMP2/MMP14/TIMP2) and ADAMTS4 and 15 preceding the expression of (MMP9/MMP13). Based on their patterns of expression, relative to the known activities of the encoded proteolytic enzymes, our results suggest that the dissolution of cartilage protoeglycans proceeds before the underlying collagenous components of the matrix are removed. The exclusion of several mRNAs that are normally expressed by osteoclasts in the profiles of mRNAs from days 3 and 10 suggests that osteoclastic activity was largely absent during the early periods of cartilage tissue formation and that proteoglycan and specific collagenase activities, precedes or is prerequisite to later osteoclast infiltration into the remodeling tissues.

ADAM Proteins↗
PubMed2006

Funding the mandate for the orthopaedic clinician scientist.

Advances in orthopaedic surgery are dependent on the creativity and innovation of individuals who have the foresight and commitment to investigate, develop and implement new technologies to improve patient care. These efforts require support and commitment from the orthopaedic community, particularly in regard to funding clinician scientists, whose scientific questions arise at the bedside. In order to support these individuals, strategic funding programs must be initiated to provide education in research methodology during medical school and orthopaedic training, establish seed and starter grants for pilot experiments, institute loan repayment programs to provide relief of the ever-growing burden of debt associated with medical education, and establish entry-level, mid-career level and established-career research support for ongoing scientific exploration. While the National Institutes of Health, Orthopaedic Research and Education Foundation, and other foundations have begun to take up these challenges, further efforts are needed in order to ensure the growth of our specialty.

Biomedical Research↗
PubMed2006

Osteogenic effects of traumatic brain injury on experimental fracture-healing.

BACKGROUND: Heterotopic bone formation has been observed in patients with traumatic brain injury; however, an association between such an injury and enhanced fracture-healing remains unclear. To test the hypothesis that traumatic brain injury causes a systemic response that enhances fracture-healing, we established a reproducible model of traumatic brain injury in association with a standard closed fracture and measured the osteogenic response with an in vitro cell assay and assessed bone-healing with biomechanical testing. METHODS: A standard closed femoral fracture was produced in forty-three Sprague-Dawley rats. Twenty-three of the rats were subjected to additional closed head trauma that produced diffuse axonal injury similar to that observed in patients with a traumatic brain injury. Twenty-one days after the procedure, all animals were killed and fracture-healing was assessed by measuring callus size and by mechanical testing. Sera from the animals were used in subsequent in vitro experiments to measure mitogenic effects on established cell lines of committed osteoblasts, fibroblasts, and mesenchymal stem cells. RESULTS: Biomechanical assessment demonstrated that the brain-injury group had increased stiffness (p = 0.02) compared with the fracture-only group. There was no significant difference in torsional strength between the two groups. Cell culture studies showed a significant increase in the proliferative response of mesenchymal stem cells after exposure to sera from the brain-injury group compared with the response after exposure to sera from the fracture-only group (p = 0.0002). This effect was not observed in fibroblasts or committed osteoblasts. CONCLUSIONS: These results support data from previous studies that have suggested an increased osteogenic potential and an enhancement of fracture-healing secondary to traumatic brain injury. Our results further suggest that the mechanism for this enhancement is related to the presence of factors in the serum that have a mitogenic effect on undifferentiated mesenchymal stem cells.

Animals↗
PubMed2006

Direct percutaneous gene delivery to enhance healing of segmental bone defects.

BACKGROUND: Healing of segmental bone defects can be induced experimentally with genetically modified osteoprogenitor cells, an ex vivo strategy that requires two operative interventions and substantial cost. Direct transfer of osteogenic genes offers an alternative, clinically expeditious, cost-effective approach. We evaluated its potential in a well-established, critical-size, rat femoral defect model. METHODS: A critical-size defect was created in the right femur of forty-eight skeletally mature Sprague-Dawley rats. After twenty-four hours, each defect received a single, intralesional, percutaneous injection of adenovirus carrying bone morphogenetic protein-2 (Ad.BMP-2) or luciferase cDNA (Ad.luc) or it remained untreated. Healing was monitored with weekly radiographs. At eight weeks, the rats were killed and the femora were evaluated with dual-energy x-ray absorptiometry, micro-computed tomography, histological analysis, histomorphometry, and torsional mechanical testing. RESULTS: Radiographically, 75% of the Ad.BMP-2-treated femora showed osseous union. Bone mineral content was similar between the Ad.BMP-2-treated femora (0.045 +/- 0.020 g) and the contralateral, intact femora (0.047 +/- 0.003 g). Histologically, 50% of the Ad.BMP-2-treated defects were bridged by lamellar, trabecular bone; the other 50% contained islands of cartilage. The control (Ad.luc-treated) defects were filled with fibrous tissue. Histomorphometry demonstrated a large difference in osteogenesis between the Ad.BMP-2 group (mean bone area, 3.25 +/- 0.67 mm(2)) and the controls (mean bone area, 0.65 +/- 0.67 mm(2)). By eight weeks, the Ad.BMP-2-treated femora had approximately one-fourth of the strength (mean, 0.07 +/- 0.04 Nm) and stiffness (mean, 0.5 +/- 0.4 Nm/rad) of the contralateral femora (0.3 +/- 0.08 Nm and 2.0 +/- 0.5 Nm/rad, respectively). CONCLUSIONS: A single, percutaneous, intralesional injection of Ad.BMP-2 induces healing of critical-size femoral bone defects in rats within eight weeks. At this time, the repair tissue is predominantly trabecular bone, has normal bone mineral content, and has gained mechanical strength.

Animals↗
PubMed2005

Effects of low-dose, intermittent treatment with recombinant human parathyroid hormone (1-34) on chondrogenesis in a model of experimental fracture healing.

Recent studies have demonstrated that intermittent administration of parathyroid hormone (PTH) enhances osteogenesis (hard callus formation) and increases mechanical strength in experimental fracture healing. Thus far, however, effects of PTH on chondrogenesis (soft callus formation) during fracture healing have not been fully elucidated. In the present study, we analyzed the underlying molecular mechanism by which exogenous PTH would affect chondrogenesis in a model of experimental fracture healing. Unilateral femoral fractures were produced in 2-month-old Sprague-Dawley rats. Daily subcutaneous injections of 10 microg/kg of recombinant human PTH(1-34) [rhPTH(1-34)] were administered over a 28-day period of fracture healing. Control animals were injected with vehicle solution (normal saline) alone. The results showed that, on day 14 after fracture, cartilage area in the PTH-treated group was significantly increased (1.4-fold) compared with the controls, but this increase was not observed at days 21 and 28. In the early stage of chondrogenesis (days 4-7), cell proliferation, expressed as the rate of proliferating cell nuclear antigen-positive cells, was increased in mesenchymal (chondroprogenitor) cells but not chondrocytes in the PTH-treated group compared with controls. In addition, gene expression of SOX-9 was up-regulated in the PTH-treated group on day 4 (1.4-fold), and this was accompanied by enhanced expression of pro-alpha1 (II) collagen (1.8-fold). After 14 days, there were no significant differences between groups in either cell proliferation or the expression levels of cartilage differentiation-related genes (SOX-9, pro-alpha1 (II) collagen, pro-alpha1 (X) collagen and osteopontin). These results suggest that intermittent treatment with low-dose rhPTH(1-34) induces a larger cartilaginous callus but does not delay chondrocyte differentiation during fracture healing.

Animals↗
PubMed2005

Application of histomorphometric methods to the study of bone repair.

Standardized methods for the histomorphometric assessment of bone are essential features of most studies of metabolic bone diseases and their treatments. These methodologies were developed to assess coupled remodeling, focusing primarily on osteoblasts and osteoclasts, the anabolic and catabolic rates of these cells, and structural features of mature bone. Research studies on bone healing and the development of new therapeutic approaches for the enhancement of bone repair also require a comprehensive understanding of the basic cellular and tissue level mechanisms that underlie these processes. However, the histological methods developed for metabolic bone disease studies are not completely suitable for studies of bone repair because they are based on assumptions that there is little variation in tissue composition within a sample of bone and not generally designed to quantify other types of tissues, such as cartilage, that contribute to bone healing. These techniques also do not provide tissue-based structural measurements that are relatable to the specific types of biomechanical and radiographic structural assessments that are used to determine rates of bone healing. These deficiencies in current histological approaches therefore point to the need to establish standardized criteria for the histomorphometric assessments that are specifically adapted for the study of bone repair in models of fracture healing and bone regeneration. In this Perspective, we outline what we believe to be the specific structural, tissue. and cellular aspects that need to be addressed to establish these standardized criteria for the histomorphometric assessment of bone repair. We present the specific technical considerations that need to be addressed to appropriately sample repair tissues to obtain statistically meaningful results and suggest specific procedures and definitions of nomenclatures for the application of this technology to bone repair. Finally, we present how aspects of histomorphometric measurements of bone repair can be related to biomechanical and radiographic imaging properties that functionally define rates of bone healing, and thus, how these tools can be used to provide corroborating data.

Animals↗
PubMed2005

Recombinant human bone morphogenetic proteins in the treatment of fractures.

Recently, several prospective randomized clinical trials have resulted in the publication of critical studies on the efficacy of recombinant human morphogenetic proteins BMP-2 (rhBMP-2) and BMP-7 (OP-1) in spinal fusion and fracture healing. The clinical use of BMPs is now in its infancy and understanding the mechanism and the appropriate application of these proteins is necessary for all practicing orthopedic surgeons. This article will revisit some of the early studies using rhBMPs and review the current literature on their role in fracture healing.

Animals↗
PubMed2005

Effect of bisphosphonates on periprosthetic bone mineral density after total joint arthroplasty. A meta-analysis.

BACKGROUND: Periprosthetic bone loss following total joint arthroplasty may threaten the survival of the implant. Bisphosphonates are effective in reducing bone loss in conditions associated with accelerated bone turnover. To determine the current understanding of the effect of bisphosphonates on periprosthetic bone mineral density after total joint arthroplasty, we conducted computerized searches for randomized controlled trials evaluating the use of bisphosphonates in patients treated with primary total joint arthroplasty. METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, the web site of the United Kingdom National Research Register, and the archives of the American Academy of Orthopaedic Surgeons annual meetings (1989 through 2003), and we conducted hand searches of the bibliographies of relevant articles. We assessed methodological quality and abstracted relevant data. When necessary, we contacted authors to provide additional information. RESULTS: Of 386 citations that were initially identified, six (five complete papers and one abstract), which included a total of 290 patients, met our inclusion criteria. Those papers showed that significantly less periprosthetic bone loss had occurred in the bisphosphonate-treated patients than in the control patients at three months (152 patients; weighted mean difference, 3.3%; 95% confidence interval, 1.9% to 4.7%; p < 0.01), six months (248 patients; weighted mean difference, 4.5%; 95% confidence interval, 1.6% to 7.4%; p < 0.001), and twelve months (197 patients; weighted mean difference, 4.2%; 95% confidence interval, 1.5% to 6.9%; p = 0.03). Bisphosphonates appeared to have a larger effect on bone loss following arthroplasties with cement than on bone loss following arthroplasties without cement (difference, 0.1%, 5%, and 5.4% at three, six, and twelve months; significant difference [p < 0.001] at one year only) and a larger effect on bone loss following total knee arthroplasties than on bone loss following total hip arthroplasties (difference, 4.1%, 11.5%, and 7.1% at three, six, and twelve months; significant difference [p < 0.001] at six months only). None of the studies related the effects of bisphosphonates on bone mineral density to clinically relevant outcomes. CONCLUSIONS: A meta-analysis of six randomized controlled trials suggested that bisphosphonates have a beneficial effect with regard to maintaining more periprosthetic bone mineral density than that in controls. However, the limitations of the available studies and the lack of analyses of clinically relevant outcomes (functional outcomes, revision rates, and quality of life) necessitate the planning and conduct of a sufficiently sized, methodologically sound study with clinically relevant end points. Until this has been done, the current evidence regarding the beneficial effects of bisphosphonates on periprosthetic bone after total joint arthroplasty should be interpreted with caution.

Arthroplasty, Replacement↗
PubMed2005

Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1-34).

BACKGROUND: Recombinant human parathyroid hormone (PTH [1-34]; teriparatide) is a new treatment for postmenopausal osteoporosis that can be systemically administered for the primary purpose of increasing bone formation. Because several studies have described the enhancement of fracture-healing and osteointegration in animals after use of PTH, we sought to critically analyze this skeletal effect. METHODS: Two hundred and seventy male Sprague-Dawley rats underwent standard, closed femoral fractures and were divided into three groups that were administered daily subcutaneous injections of 5 or 30 mug/kg of PTH (1-34) or vehicle (control). The dosing was administered for up to thirty-five days. Groups were further divided into three subgroups and were killed on day 21, 35, or 84 after the fracture. The bones were subjected to mechanical torsion testing, histomorphometric analysis, or microquantitative computed tomography. RESULTS: By day 21, calluses from the group treated with 30 mug of PTH showed significant increases over the controls with respect to torsional strength, stiffness, bone mineral content, bone mineral density, and cartilage volume. By day 35, both groups treated with PTH showed significant increases in bone mineral content and density and total osseous tissue volume, and they demonstrated significant decreases in void space and cartilage volume (p < 0.05). Torsional strength was significantly increased at this time-point in the group treated with 30 mug of PTH (p < 0.05). While dosing was discontinued on day 35, analyses performed after eighty-four days in the group treated with 30 mug of PTH showed sustained increases over the controls with respect to torsional strength and bone mineral density. No change was noted in osteoclast density at the time-points measured, suggesting that treatment with PTH enhanced bone formation but did not induce bone resorption. CONCLUSIONS: These data show that daily systemic administration of PTH (1-34) enhances fracture-healing by increasing bone mineral content and density and strength, and it produces a sustained anabolic effect throughout the remodeling phase of fracture-healing.

Anabolic Agents↗
PubMed2005

Bisphosphonates in orthopaedic surgery.

Bisphosphonates are the most clinically important class of antiresorptive agents available to treat diseases characterized by osteoclast-mediated bone resorption. Currently, seven bisphosphonates have the approval of the United States Food and Drug Administration. The most common adult diseases treated with bisphosphonates include osteoporosis, Paget disease, and metastatic bone disease. The treatment of pediatric disorders such as osteogenesis imperfecta and fibrous dysplasia with bisphosphonates has gained momentum, and initial investigations have demonstrated an acceptable safety profile. Currently, there is a lack of long-term follow-up data, which will be necessary for the development of responsible guidelines for therapy.

Adult↗
PubMed2004

Increased VEGF expression in the epiphyseal cartilage after ischemic necrosis of the capital femoral epiphysis.

UNLABELLED: Ischemic injury to the immature femoral head produces epiphyseal cartilage damage and cessation of endochondral ossification. This study suggests that VEGF facilitates the repair of the necrotic epiphyseal cartilage, which is essential for restoration of endochondral ossification and re-establishment of the growth of the immature femoral head after ischemic necrosis. INTRODUCTION: Legg-Calve-Perthes disease (LCPD) is a childhood form of osteonecrosis that produces growth arrest of the secondary center of ossification. The cessation of growth is caused by ischemic damage to the hypertrophic zone of the epiphyseal cartilage where endochondral ossification normally occurs. The role of vascular endothelial growth factor (VEGF) in restoring endochondral ossification in the epiphyseal cartilage after ischemic necrosis was investigated in a piglet model of LCPD because the resumption of normal growth is important for maintaining the spherical shape of the femoral head. MATERIALS AND METHODS: Piglet femoral heads were assessed 24 h to 8 weeks after the surgical induction of ischemia. Western blot analysis, ribonuclease protection assay (RPA), immunohistochemistry, and in situ hybridization were performed. RESULTS: Western blot analysis and RPA showed increased VEGF protein and mRNA expression, respectively, in the epiphyseal cartilage of the infarcted heads compared with the contralateral normal heads. In the normal femoral heads, VEGF-immunoreactivity (VEGF-IR) and transcripts were observed in the hypertrophic zone of the epiphyseal cartilage. In the infarcted heads, VEGF-IR and transcripts were no longer observed in the hypertrophic zone because of diffuse cell death in that zone from ischemia. However, VEGF-IR and transcripts were observed in the proliferative zone above the necrotic hypertrophic zone. At 8 weeks, vascular granulation tissue invasion of the necrotic hypertrophic zone was observed with active resorption of the necrotic cartilage. In some areas where the necrotic cartilage was completely resorbed, restoration of endochondral ossification was observed. In these areas, VEGF transcripts were observed in the newly formed hypertrophic zone. CONCLUSIONS: VEGF expression was increased, and its spatial expression was altered in the epiphyseal cartilage after ischemic necrosis of the immature femoral head. VEGF upregulation in the proliferative zone after ischemic damage may play a role in stimulating vascular invasion and granulation tissue formation in the necrotic hypertrophic zone of the epiphyseal cartilage. This may be an important step toward facilitating the resorption of the necrotic cartilage and restoration of endochondral ossification leading to further growth and development of the femoral head.

Animals↗
PubMed2004

Fidelity of Runx2 activity in breast cancer cells is required for the generation of metastases-associated osteolytic disease.

The osteolytic bone destruction associated with breast cancer skeletal metastases represents a serious and incurable clinical condition. However, the molecular mechanisms regulating tumor cell expression of factors involved in the generation of osteolytic disease remain elusive. We demonstrated recently that breast cancer cells express the Runx2 transcription factor, essential for bone formation and a regulator of skeletal homeostasis. Our experimental results demonstrate that perturbation of Runx2 regulatory function in tumor cells abolishes their ability to form osteolytic lesions in vivo. In vitro, we show that breast cancer cells inhibit osteoblast differentiation while concurrently enhancing osteoclast differentiation in marrow stromal cell cultures. Disruption of Runx2 activity abrogates both of these cancer cell-mediated effects on bone cells. These results demonstrate that Runx2 expression in breast cancer cells provides a molecular phenotype that enables the interactions between tumor cells and the bone microenvironment that lead to osteolytic disease.

Adenocarcinoma↗