Thomas A. Einhorn - US grants

DESCRIPTION (provided by applicant): Skeletal repair is a fundamental process that underlies many aspects of orthopaedic and musculoskeletal care ranging from fracture treatment to reconstructive surgery of the spine and extremities. Current estimates indicate that 5-10% of fractures experience delayed or impaired healing, 5-30% of spinal fusions fail to unite and the number of bone graft procedures performed worldwide exceeds 1.5 million per year. Thus while much has been learned regarding the biology of the bone repair process, significant gaps remain in our knowledge and a need exists for the development of strategies to enhance skeletal healing and regeneration. This application will cover areas of cell and molecular biology, biomedical engineering, and metabolic bone disease to provide a coordinated, integrated program of investigations on skeletal repair. Scientists with expertise in each of these domains will interact for the mutual gain of knowledge and synergistic development of concepts and ideas. The scientific program is composed of 3 projects and 4 cores. The projects will elucidate the mechanisms of angiogenesis in bone regeneration using a model of distraction osteogenesis, the role of BMPs in fracture healing using a novel transgenic model in which small-molecule-regulated protein dimerization is used to specifically activate a transcription factor that allows us to express noggin (an inhibitor of BMP function) or BMP2 in both in a conditional and tissue specific manner, and the effects of metabolic dysregulation on fracture healing using diabetes as a model system. The cores will provide services and databases to enhance the development of the projects. The genomics and informatics core will enhance the collection, organization and sharing of data among projects. A centralized facility for carrying out standardized measurements of skeletal healing will be established through the histomorphometry and biomechanics core. The cellular and molecular biology core will provide a centralized facility for the development and maintenance of the cellular and molecular biological reagents as well insure uniform quality control for all our surgical models. Finally, oversight and management of programmatic directives and funds and coordination of advisory input from the internal and external committees will be provided through the administrative core. The program intends to establish a more profound understanding of skeletal repair mechanisms through the integrative and collaborative activities of a team of investigators who have a track record of complimentary and synergistic scientific associations. Successful establishment and implementation of this program will greatly enhance the coordinated activities of this team of investigators and lead to important new results and directions for skeletal healing research.

Bone morphogenetic proteins (BMPs) are potent morphogens that have been shown to promote chondrogenic and osteogenic differentiation. This has been demonstrated in vitro, within model systems of mesenchymal stem cells, and in vivo when recombinant BMPs have been implanted or injected into ectopic, heterotopic or orthotopic sites. BMPs are also expressed at elevated levels throughout all stages of bone repair and have been shown, when exogenously administered, to enhance the healing response. Hypothesis: BMPs are critical in the regulation of all phases of fracture healing. In order to test this hypothesis, the studies proposed in this application will generate transgenic mice in which a novel experimental strategy is employed that restricts the expression of a transgene to either cartilage or bone and allows for the exogenous regulation of that transgene through systemic administration of a small molecule. Transgenic animals will be engineered to contain an artificial transcription factor encoded in two proteins, a novel DNA binding domain and an activation domain. The expression of these domains will be driven by a tissue-specific promoter (type II collagen for cartilage or osteocalcin for bone). The transcription factor will be activated by the exogenous administration of a dimerizing agent (rapamycin analog), which brings these domains into proximity. When activated, it will recognize a unique promoter which will drive the overexpression of BMP-2 or antagonize BMP function by overexpressing Noggin. Using this strategy, transgenic animals will undergo normal embryological development and fractures (or, in the case of Project 1, distraction osteogensis) will be carried out in the presence of normal skeletal function. Only upon introduction of the dimerizing agent will loss or gain of function states be induced through the overexpression of these transgenes. Fracture healing will then be analyzed in specific tissues and at specific times under conditions in which BMP function is altered. These studies will provide extensive new data concerning the specific roles that BMPs play at critical stages of fracture healing and establish a powerful model system for investigating a wide array of molecules and their effects on skeletal function.

DESCRIPTION (provided by applicant): Hip fractures occur in 280,000 Americans, over 5,000 per week. During the next 40 years, the number of hip fractures is likely to exceed 500,000 annually, and the estimated annual health care costs will reach a Staggering $9.8 billion. Hip fracture patients are at risk of a 30% mortality rate and impairment of independence and quality of life. Hip fractures are commonly treated with hip replacement, or arthroplasty. Two common types of arthroplasty exist, total hip arthroplasty (THA) and hemi-arthroplasty (HA). Advocates of hemi-arthroplasty (HA) focus upon reduced dislocation rates, lower rates of deep vein thrombosis, shorter operating times, less blood loss, and a technically less demanding procedure. Surgeons supporting THA perceive benefits in improving patient function and improving quality of life. Methodological limitations of previous studies, as well as their small sample sizes and resulting wide confidence intervals, have left the optimal operative approach unresolved. Objectives: In patients over 50 years who have sustained a displaced femoral neck fracture, what is the rate of re-operation at 2 years when THA versus HA is used as the surgical treatment? We will also evaluate patient function and quality of life. Study Design: To maximize the efficiency of our randomized patients, we propose an expansion of our ongoing pilot study into a vanguard phase of our proposed definitive randomized trial of 1, 316 patients, including 200 total patients in the US, who have sustained a displaced femoral neck fracture. This study will recruit 100 more patients across 12 US sites, and continue to follow the 100 patients from the pilot study. Patients will be randomized to either THA or HA and treated by surgeons with expertise in that technique. We will independently adjudicate revision surgery rates and collect functional outcome data at hospital discharge, 1 week, 10 weeks, 6-, 9-, 12-, 18- and 24-months. Hypothesis: We hypothesize that total hip arthroplasty will have similar or lower rates of re-operation (primary outcome) and higher functional outcome scores (secondary outcome) at 24 months compared with hemi-arthroplasty. This trial will not only change current orthopaedic practice, but will set a benchmark for the conduct of future orthopaedic trials.