More than 44% of individuals receiving high doses of prolonged glucocorticoid medication develop osteonecrosis, with the femoral head being the most commonly affected site, predominantly in those aged 30-40 years. In a study published in Med Research, an international team of researchers provides a systematic examination of the molecular mechanisms driving glucocorticoid-induced osteonecrosis (GION), with particular emphasis on apoptotic pathways and their therapeutic implications.
"Glucocorticoids are essential medications for treating inflammation, autoimmune diseases, and malignant tumors, but their prolonged use can lead to severe musculoskeletal complications," explains the research team. "Understanding the precise molecular mechanisms behind bone cell death is crucial for developing effective prevention and treatment strategies."
The research identifies multiple interconnected apoptotic signaling pathways involved in GION pathogenesis. Key pathways include 11β-HSD enzymes (which regulate glucocorticoid metabolism), CD95/CD95L death receptor pathway, STAT1-caspase 3 signaling, Bcl-2 subfamily proteins controlling mitochondrial membrane permeability, PI3K/Akt survival pathways, and Wnt/β-catenin signaling crucial for bone cell survival.
According to the study, patients experiencing steroid-induced osteonecrosis exhibit high occurrence of apoptotic bone cells, whereas those with post-traumatic and idiopathic necrosis show low or rare instances. The research demonstrates that GION involves the apoptosis of osteocytes and cancellous lining cells, directly affecting bone and vascular cells and causing vascular bed destruction.
The team identified several promising therapeutic approaches currently under investigation. Denosumab, a RANKL inhibitor, has shown superior efficacy in clinical trials for preventing bone failure in patients receiving glucocorticoid therapy. In landmark studies, denosumab increased spine bone mineral density by 2.3% and total hip BMD by 1.6% at 12 months in long-term glucocorticoid users. For instance, the mesenchymal stem cell (MSC) therapy, which, has demonstrated remarkable results in a 30-year follow-up study. Only 28% of MSC-treated hips collapsed compared to 72% treated with core decompression alone, with total hip replacement required in only 24% of MSC-treated hips versus 76% in controls.
The research also highlights genetic biomarkers for risk identification. Single nucleotide polymorphisms in ABCB1, PON-1, and RAPGEF5 genes have been identified as risk factors for GION. The study revealed 679 differentially expressed genes associated with GION, with ASXL1, BNIP3L, FCGR2A, and TYROBP showing substantial correlation with the condition.
Novel therapeutic strategies include targeting specific molecular pathways with natural compounds such as salidroside, allicin, and pinocembrin, which activate protective PI3K/Akt signaling. Advanced biomaterials including tetrahedral framework nucleic acids (tFNAs) and various drug delivery systems show promise for localized treatment approaches.