Largest study of genotype database of patients with avascular necrosis and matched controls suggests AVN subtype linked to steroids

Avascular necrosis (AVN) of the femoral head occurs in an estimated 20,000 new patients every year in the U.S., typically in patients younger than age 40 — a younger age than is characteristically seen among patients with primary osteoarthritis.

The condition develops when the osteocytes of trabecular bone necrose. In most patients, this is progressive and leads to collapse of the femoral head. Once this occurs, patients require definitive treatment with total hip arthroplasty (THA) for pain relief and improvement in daily function.

The pathophysiology of avascular necrosis (AVN) is not clear. The suspicion that the tendency to develop AVN is driven by patient genetic predisposition or epigenetic sensitivity to steroids is prompted by two findings:

  • AVN has multiple etiologies, yet a significant proportion of AVN burden is characterized as idiopathic.
  • While use of steroids is commonly considered a primary risk factor for AVN, data show a minority of patients on a high-dose steroid regimen actually develop AVN.

Epigenetics and steroid-sensitive subtype

This curiosity was the topic of a podium presentation by a Mayo Clinic team at the American Academy of Orthopaedic Surgeons (AAOS) annual meeting in March 2015. Conducting the world's largest study of genotype database patients with AVN compared with matched controls, the team looked for differentially expressed single nucleotide polymorphisms (SNPs) between patients with AVN and matched controls. Results reveal a link between epigenetics and steroid use that may predispose patients to develop a steroid-sensitive subtype of AVN. These data may also point the way to developing a new therapeutic risk-stratification screening prior to steroid use that could reduce the possibility of developing AVN.

Explains Rafael J. Sierra, M.D., an orthopedic surgeon at Mayo Clinic in Rochester, Minnesota: "In both cohorts, we identified multiple differentially expressed SNPs that maintained high levels of statistical significance. These markers may provide a novel platform for diagnosing genetic predisposition to AVN or epigenetic sensitivity to steroids, which may increase a patient's risk of developing AVN. As a possible practical application, if validated, these findings could be used to develop a simple screening test to stratify risk in patients prior to therapy to avoid AVN complications."

World's largest study of AVN

The research collaboration included investigators from Mayo Clinic Department of Orthopedic Surgery, Mayo Clinic Biobank and Mayo Clinic Genome Consortium. Mayo Biobank is a tissue repository that allowed genotyping of 88 AVN cases and 176 matched controls. Mayo Genome Consortium is a database of previously genotyped patients at Mayo that contributed data from an additional 102 AVN cases and 4,125 matched controls. Combined, these resources constitute the world's largest genotype database of AVN patients compared with matched controls.

Putative role for PPARG

Most interesting to the group was the finding that multiple and significant SNPs exist within a gene already associated with side effects of diabetes involving bone, the peroxisome proliferator-activated receptor gamma (PPARG) gene."The PPARG gene is of known importance for musculoskeletal tissue differentiation as well as lipid and steroid metabolism," explains Andre Terzic, M.D., Ph.D., director of the Mayo Clinic Center for Regenerative Medicine and a co-author of the study.

Currently, the PPARG gene is a target for diabetes cases that have established side effects of fatty bone marrow edema and increased fracture risk — a syndrome with similarities to AVN. "Greater understanding of our identified derangements in PPARG may establish new therapeutic targets for AVN," says Dr. Terzic.