CORR Insights®: CORR® ORS Richard A. Brand Award: Disruption in Peroxisome Proliferator-Activated Receptor- γ (PPARG) Increases Osteonecrosis Risk Through Genetic Variance and Pharmacologic Modulation (2019)

Where Are We Now? Osteonecrosis of the femoral head (ONFH) is a progressive, potentially debilitating disorder that leads to femoral head collapse and subsequent degenerative arthritis [1, 5, 6]. This disease affects individuals in the prime of their working lives, usually between 20 and 50 years of age. Bilateral in more than 50% of patients, ONFH often also is multifocal; it can occur not just in the femoral head, but also in the knee, the shoulder, and the talus, among other locations. Its etiology is multifactorial and poorly understood; contributing factors include chronic alcohol abuse, corticosteroid use, hypercoagulable states, and trauma. Inflammatory diseases such as lupus erythematosus and rheumatoid arthritis may also be associated with this condition, as are metabolic abnormalities like hyperlipidemia, Gaucher’s disease, smoking, and certain medications. However, ONFH in many patients is idiopathic, and occurs without any clear etiologic factors. Without intervention, ONFH generally progresses to femoral head collapse, degenerative arthritis and ultimately in many patients, total hip arthroplasty [1, 5, 6]. Mitigation of risk factors, and early diagnosis and treatment prior to femoral head collapse may allow us to retain a patient’s native hip joint. This is especially important in younger and more-active patients. Core decompression, with addition of concentrated cells harvested from the iliac crest improves the outcome for patients with early stage ONFH [1-3, 5]. However, identifying patients with early stage disease is difficult, because patients often do not become symptomatic until the disease is more advanced. There is now evidence that some patients with osteonecrosis have a genetic abnormality in the coagulation cascade, or in one or more biological pathways involved in cell metabolism, tissue formation and repair [4, 7]. In the current study, which won the CORR® ORS RAB Award for Orthopaedic Research, Wyles and colleagues [7] shed further light as to why some patients exposed to different risk factors for ONFH develop this condition, and why others may not. As outlined above, it has been previously suspected that metabolic abnormalities may predispose some patients to osteonecrosis. Wyles and colleagues [7] have determined that genetic mutations in Peroxisome Proliferator-Activated Receptor- γ (PPARG), a key factor in fatty acid storage and glucose metabolism, has an important relationship with the development of ONFH. Where Do We Need To Go? Despite what we know about osteonecrosis, many unanswered questions remain: Are there other genetic predispositions or abnormalities associated with osteonecrosis? Is there a final common metabolic pathway linking some or all the causes of this disease? Answers to these questions could lead to the development of diagnostic biomarkers of early disease. A mechanistic understanding of the metabolic pathways involved in osteonecrosis could lead to potential preventative and therapeutic treatments. We still need to identify and monitor “high risk” individuals, especially those who are being continuously or intermittently exposed to known adverse conditions (such as corticosteroids). Once better screening tests are developed, this high-risk population would be a good group in which we might evaluate preventative interventions. Screening methods for these patients, however, should be both evidence-based and cost-effective; as yet, these do not exist. How Do We Get There? In order to decrease the occurrence of ONFH, several avenues of investigation should be encouraged. First, biobanking of blood and other specimens including the femoral heads of patients with osteonecrosis, combined with cutting edge analytical methods (both biologically based and using “big data” computer methodologies) will help identify genetically and environmentally associated abnormalities in individuals susceptible to osteonecrosis. Then, in vitro and in vivo models (including the use of knockouts and overexpressing cells and antibodies) could be developed to determine whether a particular genetic mutation, suppressed metabolic factor, or environmental agent indeed produces ONFH. Once these predispositions and biological pathways have been identified and confirmed, reliable tests for earlier diagnosis in susceptible patients could be developed to monitor and identify patients who are at risk. Then targeted interventions, such as medications, gene therapies and other treatments can be designed to modulate or counteract the offending agent or its biological consequences. These studies would need to be carefully devised to demonstrate safety, efficacy and cost-effectiveness; suitable controls for these treatments would have to be incorporated. In the current study, the authors identified PPARG as a critical factor in the development of ONFH [7]. Thus, abnormalities in PPARG and other candidate genes/pathways yet to be discovered may be potential diagnostic markers and/or targets for individualized therapies in patients with ONFH. Potential next steps include designing in vitro and in vivo studies, as outlined above, to further substantiate the above seminal findings.