Early Detection and Monitoring of Osteonecrosis of the Femoral Head

PROJECT SUMMARY: Osteonecrosis of the femoral head [ONFH] is a crippling hip disorder affecting children and young adults that can lead to collapse of the femoral head, osteoarthritis, and the need for a hip replacement at a young age. Clinical management of young patients with early-stage ONFH focuses on preventing femoral head collapse, at which point little can be done to salvage the hip joint. However, one of the primary hip preservation treatments for early-stage ONFH, core decompression surgery (which involves drilling into the femoral head), fails to prevent disease progression in 30% or more of patients. This failure can be attributed in part to delayed diagnosis and limited ability to predict and monitor treatment response using current clinical imaging methods (radiography and conventional T1- and T2-weighted magnetic resonance imaging [MRI]). Our long-term goal is to improve clinical outcomes for children and adults with or at risk for ONFH through the synergistic advancement of imaging and therapies. The objective of this R01 proposal is to address the need for better imaging to inform treatment of early-stage ONFH by characterizing the sensitivity of advanced MRI techniques to assess bone ischemia, necrosis, and repair. Our central hypothesis is that quantitative MRI methods are sensitive in detecting early-stage ONFH and provide quantitative measures of the degree of ischemic injury and subsequent repair to the femoral head. We will build upon our promising work using a piglet model of ischemic ONFH, which has demonstrated that quantitative, non-contrast- enhanced MRI techniques, including relaxation time mapping, diffusion imaging, and perfusion imaging, are sensitive and reliable in detecting ischemic injury to the femoral head. In Aim 1, we will expand upon our piglet model studies to identify the cellular changes driving the sensitivity of the quantitative MRI methods to ischemic injury and drilling-induced repair of the femoral head. Animals will be imaged in vivo at 3T MRI, and the femoral heads will subsequently be assessed histologically. In Aims 2 and 3, we will take initial steps to clinically translate the quantitative MRI methods by conducting pilot studies to detect early-stage injury and monitor response to core decompression treatment in patients with ONFH. In Aim 2, we will evaluate whether the quantitative MRI methods can detect femoral head ischemia without use of a gadolinium contrast agent in a pilot study of children with juvenile idiopathic ONFH (also known as Legg-Calvé-Perthes disease). In Aim 3, we will evaluate whether the quantitative MRI methods can detect a reparative response to core decompression in a pilot study of adults being treated for early-stage ONFH, and whether the response differs in those patients whose treatment fails to prevent femoral head collapse versus those whose treatment is successful in preventing disease progression. Collectively, these aims are a critical step toward improving long-term outcomes for young patients with early-stage ONFH through advancement of imaging to allow for new opportunities for therapeutic intervention and the evaluation of the efficacy of new treatments.