Nontraumatic Osteonecrosis: An Early Target for Gene Therapy

As osteonecrosis of the femoral head (ONFH) progresses, it can impair a patient’s ability to walk, and hip arthroplasty is often the only effective long-term option. Other interventions to relieve the pain of ONFH include surgical decompression of the femoral head, which is generally effective but often does not change the natural history of the process. Once the femoral head collapses and loses sphericity, degenerative arthritis of the hip follows quickly. Well-documented risk factors for ONFH include excessive alcohol consumption and corticosteroid use. But why do some patients with these risk factors develop osteonecrosis, while others do not.

In the September 16, 2020 issue of The Journal, Zhang et al. address that clinical quandary with a genomewide association study on a chart-reviewed cohort of 118 patients with ONFH and >56,000 controls. The findings shed light on what is obviously a condition with multifactorial etiology and complex gene-environment interactions. The case-control study identified 1 gene (PPARGC1B) and 4 single nucleotide variants associated with ONFH overall, and with 2 subgroups—those exposed to corticosteroids and those with femoral head collapse. Steroid intake was highly prevalent in both cohorts—90.7% of the ONFH patients had at least one 3-week course of corticosteroids, compared with 68.3% of controls.

For readers interested in the detailed genetic bases for osteonecrosis, this study offers a treasure trove of data. But for all of us, these findings, after they are verified in other populations, may very well form the basis for pharmacologic and gene-modifying strategies in patients at risk for ONFH. Moreover, osteonecrosis of the femoral head is just one of many musculoskeletal conditions that can probably be addressed with this type of genome-based research strategy.

Marc Swiontkowski, MD
JBJS Editor-in-Chief