Tumor necrosis factor-alpha-mediated inflammatory bone loss: Pathogenic mechanisms and therapeutic potential of its inhibitors

Bone remodeling preserves skeletal integrity through the balanced actions of bone-resorbing osteoclasts and bone-forming osteoblasts, regulated by mechanical, endocrine, and immune signals. Tumor necrosis factor-alpha (TNF-α), a key pro-inflammatory cytokine, disrupts this balance by enhancing osteoclast differentiation and activation in synergy with receptor activator of nuclear factor κB ligand, leading to net bone loss, microarchitectural deterioration, and increased fracture risk. Epidemiological studies consistently demonstrate that TNF-α-mediated inflammatory diseases are associated with systemic reductions in bone mineral density (BMD) and heightened fracture risk. Patients with rheumatoid arthritis have approximately twice the prevalence of osteoporosis compared to the general population. Similarly, individuals with ankylosing spondylitis, psoriatic arthritis, psoriasis, or inflammatory bowel disease often present with generalized BMD loss affecting both axial and appendicular skeletons. Notably, these skeletal deficits are observed even in patients without overt joint destruction, underscoring the systemic nature of TNF-α-driven bone pathology. Biological TNF-α inhibitors - etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol - were primarily developed to control inflammation but have also demonstrated potential skeletal benefits, such as preservation or modest improvement in BMD and favorable modulation of bone turnover markers. This review synthesizes mechanistic and clinical evidence on TNF-α-mediated bone loss across diverse inflammatory diseases, evaluates the bone-protective potential of TNF-α inhibitors, and highlights shared pathogenic mechanisms and therapeutic considerations to guide future research.