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

Abstract

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.

Introduction

With the increase in life expectancy and population aging, the prevalence of osteoporosis (OP) makes it a global health concern and a significant societal burden (Liu, Guo, Xu, et al., 2022). OP is a systemic skeletal disease featured with low bone mass, deteriorative bone microstructure, and enhanced fracture susceptibility, leading to high rate of mortality and disability in OP patients (Z. Xu et al., 2024). Approximately 8.9–10.0 million fractures occurred among the 200 million OP patients, with the estimated treatment cost of $200–$300 billion annually worldwide (Z. Xu et al., 2024; Yan Zhang, Zheng, & Liu, 2024). OP takes its rise from the disequilibrium between osteoclast-dependent bone resorption (osteoclastogenesis) and osteoblast-dependent bone formation (osteogenesis), which can be induced by multiple physiological and environmental factors such as aging, unhealthy lifestyle, endocrine disorders (e.g., parathyroid hormone, sex hormones, 1,25-dihydroxyvitamin D3, and calcitonin), limb disuse, and nutrient deficiencies/malabsorption, etc. (Lopes et al., 2022; Zhang, Song, et al., 2024a). Conventionally, OP and its complications (fractures, disability and chronic pain) are controlled predominantly by clinical drugs, including osteoanabolic and antiresorptive agents (Malluche et al., 2022).

However, patients are increasingly concerned about the pharmacological risks associated with the prolonged drug administration such as carcinogenesis (osteosarcoma), chondro-calcification, gastrointestinal reactions, jaw bone necrosis, and cardiovascular diseases (chronic liver disease), etc. (Zhang, Zheng, & Liu, 2024) Therefore, intervention of dietary nutrients rather than pharmacological agents has recently aroused increasing interest as a safer curative strategy against OP due to the urgent requirement for healthy & nutrition-oriented products (Liu et al., 2022, Liu et al., 2022). Bone is a highly mineralized connective tissue composed of hydroxyapatite (calcium/phosphorus) and collagen. Increasing evidence supports that dietary nutrients such as vitamins, minerals, phytoestrogens, and collagen peptides (CPs) are effective and safe for bone health by systemically regulating the bone remodeling process (Liu et al., 2022, Liu et al., 2022). Globally, peptide therapeutics are expected to grow at a rate of 9% annually from 2016 to 2024 (Anand et al., 2023).

CPs, consisting of 2–20 amino acids (oligopeptides) or more (polypeptides), have aroused extensive interests in bone health-care sector (∼48%) and food (∼32%) industries owing to their splendid bioavailability, including superior solubility/absorptivity, low toxicity/allergenicity, and broad-spectrum bioactivities such as antioxidant, antibacterial, angiotensin converting enzyme inhibitory (ACEI) and immunomodulating activity, etc. (H. Liu, Guo, Xu et al., 2022) More essentially, accumulating in vitro and in vivo evidences testify that dietary intervention with CPs exhibited fantastic anti-osteoporotic bioactivity, that’s, collagen anti-osteoporotic peptides (CAPs), and CAPs are widely used as therapeutic agents. For example, Yang et al. found that CAPs enhanced osteogenesis and suppressed osteoclastogenesis by activating the BMP/Smad and Wnt/β-catenin signaling pathways in ovariectomized mice (Q. Yang et al., 2024). Similarly, Li et al. believed that yak bone collagen peptides (1000–3000 Da) could significantly enhanced bone microstructure of OP mouse (N. Li et al., 2025). Accumulating evidence indicates that the potential of CAPs in regulating abnormal bone remodeling may originate from their specific amino acid sequence or composition, offering a safe and cost-effective strategy for OP management compared with traditional medical therapies (Y. Zhang et al., 2024). However, the research and development of CAPs still lacks systematicity and depth/breadth.

Herein, this review generalizes the current updates concerning CAPs, with emphasis on their discovery strategies, underlying anti-osteoporotic mechanisms, and structure-(anti-osteoporotic) bioactivity relationship. We intend to present an inclusive and up-to-date overview, and propose systematic theoretical support for the efficient application of CAPs in bone health functional foods and pharmaceuticals for OP management.

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Hong Liu, Shan He, Jun Yang, Chengcheng Lin, Bo Tang, Yixue Hou, Liping Yan, Qianhui Fang, Xiaolu Wang, Weijing Li, YuanXi Deng, Long Ma, Shuyi Qian, Bin Zhang, Comprehensive review on the collagen anti-osteoporotic peptides: Discovery strategies, underlying mechanisms and structure-bioactivity relationship, Journal of Functional Foods, Volume 142, 2026, 107321, ISSN 1756-4646, https://doi.org/10.1016/j.jff.2026.107321.

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