Screening for Biomarkers of Osteonecrosis of the Femoral Head

Osteonecrosis of the Femoral Head (ONFH) is a highly disabling disease characterized by osteocyte death caused by interrupted blood supply to the femoral head. The natural course of ONFH progresses rapidly. Femoral head collapse can occur within approximately two years, and ultimately about 30% of patients require total hip arthroplasty. This disease not only severely impairs patients' quality of life but also imposes a heavy medical and economic burden. The global incidence of ONFH is on the rise. Statistics show that there are approximately 20,000 to 30,000 new cases annually in the United States, and around 300,000 new cases in China each year, with young and middle-aged people accounting for the largest proportion. The incidence rate among individuals aged 15 years and above is approximately 10-30 per 100,000 population. The prevalence of ONFH is higher in northern regions than in southern areas, and higher in urban than in rural areas. Such distribution differences may be associated with climate, occupation, medical accessibility, and exposure levels of risk factors.

The etiology and pathogenesis of ONFH are complex and correlated with multiple risk factors including excessive alcohol consumption, glucocorticoid administration, and hip fractures. Long-term or high-dose glucocorticoid use is a major predisposing factor for ONFH, accounting for approximately 40% of all cases. Glucocorticoids may induce femoral head ischemia and subsequent necrosis by increasing blood viscosity, triggering fat embolism, or directly damaging vascular endothelial cells. Long-term heavy drinking (average daily alcohol intake ≥ 40 g) is another high-risk factor, responsible for 20%-30% of cases. Alcohol inhibits osteoblast activity, exacerbates oxidative stress, and disrupts bone microcirculation through lipid metabolism disorders. Traumatic injuries such as femoral neck fracture and hip dislocation directly damage the retinacular blood vessels, contributing to 10%-20% of ONFH cases. Subcapital fractures carry the highest risk of osteonecrosis; completely displaced adduction fractures with severe vascular injury present a necrosis rate of 30%-50%. Delayed reduction (> 24 hours) and improper reduction operations (e.g., excessive traction) after fracture also markedly increase the risk of necrosis. In addition, metabolic disorders including hypertension, diabetes and hyperlipidemia impair bone blood circulation indirectly by exacerbating systemic angiopathy. Cigarette smoking (nicotine) induces vasoconstriction and endothelial dysfunction, thereby accelerating the progression of osteonecrosis. Osteoporosis reduces bone mineral density and the mechanical strength of the femoral head, rendering it susceptible to microfractures caused by minor trauma and further aggravating blood perfusion disturbance.

A variety of therapeutic approaches are available for ONFH, including non-surgical treatments (protective weight-bearing, bisphosphonate medication, hyperbaric oxygen therapy, and platelet-rich plasma treatment), femoral head-preserving surgeries (core decompression, vascularized bone grafting, non-vascularized bone grafting, and stem cell therapy), and emerging experimental therapies such as M2 macrophage-derived exosomes. Treatment efficacy is mainly determined by disease stage, intervention strategies and individual patient differences. Early intervention can significantly improve clinical prognosis, whereas advanced ONFH often requires complex surgical procedures such as total hip arthroplasty. Nevertheless, the early diagnostic rate of ONFH remains low, with only 68.43% of cases correctly diagnosed at the first visit. Meanwhile, the disease has a high misdiagnosis rate and is frequently misdiagnosed as lumbar disc herniation or simple arthritis.

Existing studies on ONFH are predominantly clinical research with notable limitations. Most studies adopt a single research methodology that merely analyzes ONFH from the perspective of biomechanics, while ignoring the interactions of multiple factors such as heredity, metabolism and immunity. Research designs represented by retrospective studies are prone to selection bias and information bias, which limit the generalizability of research findings. In addition, small sample sizes fail to accurately reflect the overall characteristics and epidemiological patterns of ONFH. Furthermore, inconsistent research designs in previous studies lead to heterogeneous indicators and poor data comparability. Therefore, disease-specialized research on ONFH is urgently needed. By adopting a multicenter prospective design, high-risk factors, clinical imaging data and biological samples will be systematically collected. Combined with multi-dimensional influencing factors including biomechanics, biochemistry and genetics, this study aims to explore early diagnostic biomarkers and optimal diagnostic strategies for ONFH, so as to provide evidence for optimizing clinical diagnosis and treatment protocols and establishing individualized predictive models.