Interleukin-6 and tumor necrosis factor-α in osteoimmunology: Aging, and anticytokine therapies

Table 4 Emerging and experimental therapies with current evidence level

Strategy	Representative agents/approach	Current evidence level (per manuscript)
Senolytics/SASP modulation	Dasatinib + quercetin (D+Q), navitoclax, fisetin	Preclinical (murine) efficacy; early-stage human trials show reduced inflammatory biomarkers and improved physical function, but no conclusive skeletal benefit established in humans
Downstream pathway inhibition	NF-κB/IKK inhibitors; JAK inhibitors (baricitinib, tofacitinib, upadacitinib)	JAK inhibitors reduce bone erosion in RA trials; NF-κB inhibitors effective in preclinical models; long-term safety surveillance required
Combination therapy	Anti-cytokine agent with anabolic agents (PTH analogs teriparatide/abaloparatide; romosozumab)	Preliminary/investigational; small studies (e.g., tocilizumab + romosozumab) suggest added benefit; requires confirmation in adequately powered trials
Dual cytokine inhibition	Combined TNF-α and IL-6 blockade	Conceptual; requires extensive safety evaluation due to cumulative immunosuppression
Precision/biomarker-guided therapy	Cytokine profiling, pharmacogenomics (SNPs), multi-omics, circulating miRNAs/exosomal markers, machine learning	Emerging; predictive biomarkers require validation in prospective trials

IKK: Inhibitor of IκB kinase; SASP: Senescence-associated secretory phenotype; NF-κB: Nuclear factor-κB; JAK: Janus kinase; RA: Rheumatoid arthritis; PTH: Parathyroid hormone; TNF-α: Tumor necrosis factor-α; IL-6: Interleukin-6; SNP: Single-nucleotide polymorphism.