The role of probiotics in modulating RANKL in osteoporosis: A systematic review of animal interventional studies and RCTs.

Background: Osteoporosis is a major global health concern characterized by reduced bone mass and structural deterioration. The RANK/RANKL/OPG signaling pathway plays a pivotal role in bone remodeling, particularly in osteoclastogenesis. Emerging evidence suggests that probiotics may modulate this pathway through the gut-bone axis, offering potential therapeutic benefits for bone loss.

Objective: This systematic review aims to evaluate the effects of probiotic supplementation on Receptor activator of nuclear factor kappa-Β ligand (RANKL) in animal and human interventional studies related to osteoporotic conditions.

Methods: A comprehensive literature search was conducted in PubMed, Scopus, and Google Scholar databases up to June 2025. Original interventional studies published in English, including both animal and human models, were selected according to predefined inclusion and exclusion criteria. The selection process followed PRISMA guidelines. Studies were assessed for quality by independent reviewers, and relevant data were extracted for synthesis.

Results: A total of 24 studies met the inclusion criteria, most using ovariectomized rodent models and two randomized controlled trials in postmenopausal women. Several probiotic strains-particularly Lactobacillus plantarum, Lactobacillus reuteri, Lactobacillus casei, and Bifidobacterium longum-significantly reduced RANKL expression in animal models, whereas human trials yielded limited or no effect on RANKL despite improvements in other bone turnover markers.

Conclusion: Probiotic interventions appear to exert beneficial effects on bone metabolism by modulating RANKL, particularly in estrogen-deficiency-induced osteoporosis models. However, findings from human trials remain limited and inconsistent. Further high-quality RCTs are warranted to confirm these effects and determine optimal strains, dosages, and treatment durations.