Comprehensive review on the collagen anti-osteoporotic peptides: Discovery strategies, underlying mechanisms and structure-bioactivity relationship

As global public health issue, osteoporosis (OP) has been conventionally managed with osteoanabolic/antiresorptive drugs with side effect. Recently, collagen peptides intervention has emerged as a safe and efficient alternative strategy with desirable anti-osteoporotic bioactivity. This review comprehensively summarizes the latest advances in the bioavailability of collagen anti-osteoporotic peptides (CAPs), focusing on the discovery strategies, underlying anti-osteoporotic mechanism and structure-(anti-osteoporotic) bioactivity relationship of CAPs. In silico techniques with in vitro/ vivo assays and emerging organoid (bone-on-a-chip system) provides a potent strategy for high-throughput CAPs discovery. CAPs can directly promote osteogenesis or inhibit osteoclastogenesis by regulating bone metabolism signaling pathways, or indirectly modulate bone remodeling by enhancing calcium absorption, regulating gut microbiota and metabolites (gut-bone axis), alleviating oxidative stress and suppressing inflammation. Specific conformational features potentially responsible for CAP anti-osteoporotic bioactivity are also discussed. However, further clarification (e.g., long-term interventions stability, execution of large-scale trials, and clinical translation safety, etc.) is needed to realize the efficient implementation of CAPs as ingredient for functional foods or potential pharmaceutical candidates in OP prevention.